VCV001805487.4 - ClinVar

NM_005262.3(GFER):c.258+1G>A

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.

(2)

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_005262.3(GFER):c.258+1G>A

Variation ID: 1805487 Accession: VCV001805487.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 1984477 (GRCh38) [ NCBI UCSC ] 16: 2034478 (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	Dec 24, 2022	Feb 28, 2024	Jul 21, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_005262.3:c.258+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000016.10:g.1984477G>A
NC_000016.9:g.2034478G>A
NG_016288.1:g.5329G>A

Protein change

Other names

Canonical SPDI

NC_000016.10:1984476:G:A

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.

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

Links

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.
GFER		-	-	GRCh38 GRCh38 GRCh37	91	209
LOC130058203	-	-	-	GRCh38 GRCh38	-	72

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.
Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome	Uncertain significance (1)	criteria provided, single submitter	May 25, 2020	RCV002471905.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 21, 2022	RCV002573620.3

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 (May 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767532.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: A heterozygous canonical splice site variant was identified, NM_005262.2(GFER):c.258+1G>A in intron 1 of 2 of the GFER gene. This substitution is predicted to cause aberrant … (more) A heterozygous canonical splice site variant was identified, NM_005262.2(GFER):c.258+1G>A in intron 1 of 2 of the GFER gene. This substitution is predicted to cause aberrant splicing of exon 1 in the GFER gene, affecting protein function; further testing via RNA studies are required to confirm if splicing is altered. The nucleotide at this position has high conservation (PhyloP UCSC). In silico software predicts the disruption of the donor splice site (NetGene2, Human Splicing Finder). The variant is present in the gnomAD population database at a frequency 0.0006% (1 heterozygote; 0 homozygotes). An alternative nucleotide change to cytosine at the same location has also been reported in the gnomAD database at a frequency of 0.0006%. The variant has not been previously observed in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE. (less)
Uncertain significance (Jul 21, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002968032.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 16199547 Comment: 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 … (more) 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GFER-related conditions. This sequence change affects a donor splice site in intron 1 of the GFER gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in GFER cause disease. (less)

Comment:

A heterozygous canonical splice site variant was identified, NM_005262.2(GFER):c.258+1G>A in intron 1 of 2 of the GFER gene. This substitution is predicted to cause aberrant splicing of exon 1 in the GFER gene, affecting protein function; further testing via RNA studies are required to confirm if splicing is altered. The nucleotide at this position has high conservation (PhyloP UCSC). In silico software predicts the disruption of the donor splice site (NetGene2, Human Splicing Finder). The variant is present in the gnomAD population database at a frequency 0.0006% (1 heterozygote; 0 homozygotes). An alternative nucleotide change to cytosine at the same location has also been reported in the gnomAD database at a frequency of 0.0006%. The variant has not been previously observed in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE.

Comment:

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GFER-related conditions. This sequence change affects a donor splice site in intron 1 of the GFER gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in GFER cause disease.

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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005262.3(GFER):c.258+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...