rs201386977
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_032119.4(ADGRV1):c.11974G>A(p.Asp3992Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,578,446 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D3992D) has been classified as Likely benign.
Frequency
Consequence
NM_032119.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADGRV1 | NM_032119.4 | c.11974G>A | p.Asp3992Asn | missense_variant | 58/90 | ENST00000405460.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADGRV1 | ENST00000405460.9 | c.11974G>A | p.Asp3992Asn | missense_variant | 58/90 | 1 | NM_032119.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00131 AC: 199AN: 151994Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00148 AC: 292AN: 196962Hom.: 0 AF XY: 0.00151 AC XY: 158AN XY: 104866
GnomAD4 exome AF: 0.00131 AC: 1863AN: 1426336Hom.: 5 Cov.: 29 AF XY: 0.00133 AC XY: 937AN XY: 705916
GnomAD4 genome ? AF: 0.00131 AC: 199AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95AN XY: 74332
ClinVar
Submissions by phenotype
not provided Uncertain:7Benign:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 12, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 26, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2019 | This variant is associated with the following publications: (PMID: 25262649, 25404053, 27460420, 22952768, 30245029, 31047384, 32707200) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ADGRV1 p.Asp3992Asn variant was identified in 2 of 896 proband chromosomes (frequency: 0.002) from individuals or families with Usher syndrome (Eandi_2017_PMID:29142287; Bonnet_2016_PMID:27460420). The variant was also identified in dbSNP (ID: rs201386977), ClinVar (classified as a VUS by GeneDx, EGL Genetics, Athena Diagnostics, ARUP and Praxis fuer Humangenetik Tuebingen and as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0. The variant was not identified in Cosmic. The variant was identified in control databases in 320 of 228350 chromosomes at a frequency of 0.001401 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 54 of 9380 chromosomes (freq: 0.005757), Latino in 60 of 28672 chromosomes (freq: 0.002093), Other in 11 of 6242 chromosomes (freq: 0.001762), European (non-Finnish) in 168 of 99320 chromosomes (freq: 0.001692), South Asian in 19 of 25506 chromosomes (freq: 0.000745), European (Finnish) in 5 of 22700 chromosomes (freq: 0.00022) and African in 3 of 20596 chromosomes (freq: 0.000146), while the variant was not observed in the East Asian population. The p.Asp3992 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 23, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Usher syndrome type 2C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 14, 2013 | p.Asp3992Asn in exon 58 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.4% (59/15416) of European chrom osomes and in 0.4% (4/944) of Latino chromosomes by the Exome Aggregation Consor tium (http://exac.broadinstitute.org/; dbSNP rs201386977). - |
ADGRV1-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 05, 2019 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at