chr5-90652372-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_032119.4(ADGRV1):c.3443G>A(p.Gly1148Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,603,510 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032119.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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ADGRV1 | ENST00000405460.9 | c.3443G>A | p.Gly1148Asp | missense_variant | Exon 19 of 90 | 1 | NM_032119.4 | ENSP00000384582.2 | ||
ADGRV1 | ENST00000640403.1 | c.746G>A | p.Gly249Asp | missense_variant | Exon 9 of 29 | 5 | ENSP00000492531.1 | |||
ADGRV1 | ENST00000504142.2 | n.2209G>A | non_coding_transcript_exon_variant | Exon 13 of 14 | 5 | |||||
ADGRV1 | ENST00000639676.1 | n.1041G>A | non_coding_transcript_exon_variant | Exon 7 of 11 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00160 AC: 243AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00182 AC: 445AN: 243888Hom.: 1 AF XY: 0.00192 AC XY: 253AN XY: 131982
GnomAD4 exome AF: 0.00233 AC: 3387AN: 1451312Hom.: 8 Cov.: 31 AF XY: 0.00240 AC XY: 1727AN XY: 720816
GnomAD4 genome AF: 0.00160 AC: 243AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107AN XY: 74412
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
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This variant is associated with the following publications: (PMID: 25133751, 28041643, 27068579, 25404053, 24154662) -
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not specified Benign:3
p.Gly1148Asp in exon 19 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.3% (50/16450) of South Asian ch romosomes and 0.2% (149/66614) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200945405). -
Variant summary: ADGRV1 c.3443G>A (p.Gly1148Asp) results in a non-conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 domain (IPR003644) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 243888 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.0018 vs 0.0054). c.3443G>A has been reported in the literature primarily in settings of multigene panel sequencing in individuals affected with retinopathies and/or deafness without strong evidence for causality and in at least one case where an alternative cause for the phenotype was identified (e.g. Aparisi_2014, Wang_2014, Watson_2014, Sommen_2016, Zampaglione_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as either VUS (n=4), likely benign (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
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Usher syndrome Pathogenic:1
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Usher syndrome type 2C Uncertain:1
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. -
Retinal dystrophy Uncertain:1
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ADGRV1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at