VCV000216677.29 - ClinVar

NM_012144.4(DNAI1):c.1948C>T (p.Arg650Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012144.4(DNAI1):c.1948C>T (p.Arg650Cys)

Variation ID: 216677 Accession: VCV000216677.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 34517414 (GRCh38) [ NCBI UCSC ] 9: 34517412 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	May 1, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_012144.4:c.1948C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036276.1:p.Arg650Cys	missense
NM_001281428.2:c.1960C>T	NP_001268357.1:p.Arg654Cys	missense
NC_000009.12:g.34517414C>T
NC_000009.11:g.34517412C>T
NG_008127.1:g.63602C>T

... more HGVS ... less HGVS

Protein change

R650C, R654C

Other names

Canonical SPDI

NC_000009.12:34517413:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00080 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00022

The Genome Aggregation Database (gnomAD), exomes 0.00025

The Genome Aggregation Database (gnomAD) 0.00034

Trans-Omics for Precision Medicine (TOPMed) 0.00040

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00080

Links

ClinGen: CA338457 dbSNP: rs140820295 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DNAI1		-	-	GRCh38 GRCh37	884	967

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary ciliary dyskinesia	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 18, 2022	RCV000199193.11
Kartagener syndrome	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000665810.9
Male infertility	Uncertain significance (1)	no assertion criteria provided	Jul 1, 2020	RCV001283733.2
Infertility disorder	Uncertain significance (1)	no assertion criteria provided	-	RCV001327957.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 18, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000255000.5 First in ClinVar: Oct 11, 2015 Last updated: Nov 11, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 650 of the DNAI1 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 650 of the DNAI1 protein (p.Arg650Cys). This variant is present in population databases (rs140820295, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAI1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Mar 24, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Kartagener syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000789989.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Kartagener syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001328077.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jul 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Kartagener syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001786952.1 First in ClinVar: Aug 18, 2021 Last updated: Aug 18, 2021	Sex: mixed
Uncertain significance (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Kartagener syndrome Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV004239043.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: This DNAI1 missense variant (rs140820295) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 698/1614192 total alleles; 0.04%; no homozygotes). It has been reported … (more) This DNAI1 missense variant (rs140820295) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 698/1614192 total alleles; 0.04%; no homozygotes). It has been reported in ClinVar (Variation ID 216677), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be deleterious, and the arginine residue at this position is evolutionarily conserved across most of the species assessed. We consider the clinical significance of c.1948C>T in DNAI1 to be uncertain at this time. (less)
Uncertain significance (Mar 22, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002723998.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.1948C>T (p.R650C) alteration is located in exon 19 (coding exon 19) of the DNAI1 gene. This alteration results from a C to T substitution … (more) The c.1948C>T (p.R650C) alteration is located in exon 19 (coding exon 19) of the DNAI1 gene. This alteration results from a C to T substitution at nucleotide position 1948, causing the arginine (R) at amino acid position 650 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (-)	no assertion criteria provided Method: provider interpretation	Infertility disorder Affected status: yes Allele origin: germline	MAGI's Lab - Research, MAGI Group Accession: SCV001432735.1 First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021
Uncertain significance (Jul 01, 2020)	no assertion criteria provided Method: provider interpretation	Male infertility Affected status: yes Allele origin: germline	MAGI's Lab - Research, MAGI Group Accession: SCV001432676.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: DOI: 10.3389/fendo.2020.605237 DOI: 10.3389/fendo.2020.605237
Uncertain significance (Jan 16, 2020)	no assertion criteria provided Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002085179.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 650 of the DNAI1 protein (p.Arg650Cys). This variant is present in population databases (rs140820295, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAI1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This DNAI1 missense variant (rs140820295) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 698/1614192 total alleles; 0.04%; no homozygotes). It has been reported in ClinVar (Variation ID 216677), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be deleterious, and the arginine residue at this position is evolutionarily conserved across most of the species assessed. We consider the clinical significance of c.1948C>T in DNAI1 to be uncertain at this time.

Comment:

The c.1948C>T (p.R650C) alteration is located in exon 19 (coding exon 19) of the DNAI1 gene. This alteration results from a C to T substitution at nucleotide position 1948, causing the arginine (R) at amino acid position 650 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Male Infertility Diagnosis: Improvement of Genetic Analysis Performance by the Introduction of Pre-Diagnostic Genes in a Next-Generation Sequencing Custom-Made Panel.	Precone V	Frontiers in endocrinology	2021	DOI: 10.3389/fendo.2020.605237

Text-mined citations for rs140820295 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_012144.4(DNAI1):c.1948C>T (p.Arg650Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140820295 ...