ClinVar Genomic variation as it relates to human health
NM_000969.5(RPL5):c.169_172del (p.Asn57fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000969.5(RPL5):c.169_172del (p.Asn57fs)
Variation ID: 579583 Accession: VCV000579583.33
- Type and length
-
Deletion, 4 bp
- Location
-
Cytogenetic: 1p22.1 1: 92833637-92833640 (GRCh38) [ NCBI UCSC ] 1: 93299194-93299197 (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 10, 2018 Apr 15, 2024 Sep 23, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000969.5:c.169_172del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000960.2:p.Asn57fs frameshift NM_000969.5:c.169_172delAACA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_000969.3:c.169_172del NM_001252273.2:c.475-606_475-603del intron variant NR_146333.1:n.298_301del non-coding transcript variant NC_000001.11:g.92833640_92833643del NC_000001.10:g.93299197_93299200del NG_011779.2:g.6655_6658del NG_033051.1:g.132883_132886del LRG_1155:g.6655_6658del LRG_1155t1:c.169_172del LRG_1155p1:p.Asn57fs - Protein change
- N57fs
- Other names
- -
- Canonical SPDI
- NC_000001.11:92833636:ACAAACA:ACA
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
---|---|---|---|---|---|---|
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. |
|||
DIPK1A | - | - |
GRCh38 GRCh37 |
6 | 281 | |
RPL5 | - | - |
GRCh38 GRCh37 |
33 | 308 |
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. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2022 | RCV000702906.19 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 13, 2019 | RCV000761557.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 4, 2019 | RCV001008074.23 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 23, 2022 | RCV002249419.10 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Mar 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Diamond-Blackfan anemia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000889935.1
First in ClinVar: Mar 24, 2019 Last updated: Mar 24, 2019 |
Comment:
The p.N57Qfs*12 variant in the RPL5 gene is a de novo frameshift variant, which is absent in the gnomAD database and has previously been reported … (more)
The p.N57Qfs*12 variant in the RPL5 gene is a de novo frameshift variant, which is absent in the gnomAD database and has previously been reported as a pathogenic variant in the ClinVar database (Accession: RCV000702906.1). In summary, the p.N57Qfs*12 variant meets the ACMG criteria to be classified as pathogenic based upon inheritance model, absence from controls and previous ClinVar submission. (less)
Clinical Features:
Leukopenia (present) , Microspherocytosis (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Indian
Geographic origin: India
Method: Targeted gene sequencing: Selective capture and sequencing of the protein coding regions of the genome/genes is performed. Mutations identified in the exonic regions are generally actionable compared to variations that occur in non-coding regions. Targeted sequencing represents a cost-effective approach to detect variants present in multiple/large genes in an individual. DNA extracted from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. The sequences obtained are aligned to human reference genome using BWA program and analysed using Picard and GATK version 3.6 to identify variants relevant to the clinical indication. We follow the GATK best practices framework for identification of variants in the sample. Gene annotation of the variants is performed using VEP program against the Ensembl release 87 human gene model. Clinically relevant mutations were annotated using published variants in literature and a set of diseases databases - ClinVar, OMIM, GWAS, HGMD and SwissVar. Common variants are filtered based on allele frequency in 1000 Genome Phase 3, ExAC, EVS, dbSNP147 and 1000 Japanese Genome. Non-synonymous variants effect is calculated using multiple algorithms such as PolyPhen-2, SIFT, Mutation Taster2, Mutation Assessor and LRT. Only non-synonymous and splice site variants found in the clinical exome panel consisting of 8332 genes were used for clinical interpretation. Silent variations that do not result in any change in amino acid in the coding region are not reported.
|
|
Pathogenic
(Feb 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001167812.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
The c.169_172delAACA variant has been reported previously in association with Diamond-Blackfan anemia, including an apparently de novo occurrence (Cmejla et al., 2009; Quarello et al., … (more)
The c.169_172delAACA variant has been reported previously in association with Diamond-Blackfan anemia, including an apparently de novo occurrence (Cmejla et al., 2009; Quarello et al., 2010; Gerrard et al., 2013). The deletion causes a frameshift starting with codon Asparagine 57, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Asn57GlufsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider the variant to be pathogenic. (less)
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Diamond-Blackfan anemia 6
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518994.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Pathogenic
(Sep 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Diamond-Blackfan anemia
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002710870.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.169_172delAACA pathogenic mutation, located in coding exon 3 of the RPL5 gene, results from a deletion of 4 nucleotides between nucleotide positions 169 and … (more)
The c.169_172delAACA pathogenic mutation, located in coding exon 3 of the RPL5 gene, results from a deletion of 4 nucleotides between nucleotide positions 169 and 172, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported as a sporadic or de novo occurrence in multiple DBA patients with associated congenital anomalies. One individual, diagnosed at birth, was reported to have partial anomalous pulmonary venous return and to be unresponsive to steroid therapy (Gazda HT, Am. J. Hum. Genet. 2008 Dec; 83(6):769-80). A patient with flat thenar eminence, grouped carpal bones, and short stature, and another with intellectual disability, myelomeningocele, cleft palate, and facial dysmorphism, have been reported (Quarello P, Haematologica 2010 Feb; 95(2):206-13; Boria I, Hum. Mutat. 2010 Dec; 31(12):1269-79). In a cohort of Czech DBA patients, an individual small for gestational age with flat thenar and facial dysmorphism was described (Cmejla R, Hum. Mutat. 2009 Mar; 30(3):321-7). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Sep 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Diamond-Blackfan anemia 6
Affected status: yes
Allele origin:
de novo
|
Eurofins-Biomnis
Accession: SCV003935092.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
|
|
Pathogenic
(Feb 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Diamond-Blackfan anemia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000831781.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 579583). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 579583). This variant is also known as 166_169del (56_57del). This premature translational stop signal has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 19061985, 19773262, 20960466, 23718193). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn57Glufs*12) in the RPL5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPL5 are known to be pathogenic (PMID: 19061985, 19773262). (less)
|
|
Pathogenic
(Jun 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245631.20
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
|
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
Unknown function
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000889935.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Target enrichment and high-throughput sequencing of 80 ribosomal protein genes to identify mutations associated with Diamond-Blackfan anaemia. | Gerrard G | British journal of haematology | 2013 | PMID: 23718193 |
The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update. | Boria I | Human mutation | 2010 | PMID: 20960466 |
Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations. | Quarello P | Haematologica | 2010 | PMID: 19773262 |
Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia. | Cmejla R | Human mutation | 2009 | PMID: 19191325 |
Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. | Gazda HT | American journal of human genetics | 2008 | PMID: 19061985 |
Text-mined citations for rs1558284033 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.