rs199499672

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032119.4(ADGRV1):​c.9643G>A​(p.Glu3215Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000306 in 1,610,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

1
8
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:1

Conservation

PhyloP100: 5.87
Variant links:
Genes affected
ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2791213).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADGRV1NM_032119.4 linkuse as main transcriptc.9643G>A p.Glu3215Lys missense_variant 45/90 ENST00000405460.9 NP_115495.3 Q8WXG9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADGRV1ENST00000405460.9 linkuse as main transcriptc.9643G>A p.Glu3215Lys missense_variant 45/901 NM_032119.4 ENSP00000384582.2 Q8WXG9-1

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000945
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.000960
GnomAD3 exomes
AF:
0.000290
AC:
72
AN:
248528
Hom.:
0
AF XY:
0.000311
AC XY:
42
AN XY:
134846
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000204
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000460
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.000443
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000315
AC:
459
AN:
1458406
Hom.:
0
Cov.:
29
AF XY:
0.000328
AC XY:
238
AN XY:
725554
show subpopulations
Gnomad4 AFR exome
AF:
0.0000899
Gnomad4 AMR exome
AF:
0.000247
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000454
Gnomad4 FIN exome
AF:
0.0000376
Gnomad4 NFE exome
AF:
0.000350
Gnomad4 OTH exome
AF:
0.000216
GnomAD4 genome
AF:
0.000223
AC:
34
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000945
Gnomad4 NFE
AF:
0.000382
Gnomad4 OTH
AF:
0.000475
Alfa
AF:
0.000327
Hom.:
0
Bravo
AF:
0.000223
ExAC
AF:
0.000348
AC:
42
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 20, 2015- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 15, 2024Identified in the heterozygous state in a patient with epilepsy and cardiac conduction disorder in published literature (PMID: 29261713); Identified as a single heterozygous variant in a patient with panuveitis in published literature (PMID: 32707200); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29261713, 32707200) -
Usher syndrome type 2C Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchLaboratory of Prof. Karen Avraham, Tel Aviv UniversityDec 26, 2024The ADGRV1 c.9643G>A:p.(Glu3215Lys) heterozygous variant is very rare and predicted deleterious. This variant was classified as likely pathogenic by Deafness Variation Database, and according to ClinVar SCV000063351.5, it was detected in hearing impaired individuals. In our study, it was detected in an individual with sloping normal-to-severe HL, that carried another variant in USH1G,c.955A>G:p.(Arg319Gly), suggesting digenic inheritance. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 25, 2018The p.Glu3215Lys variant in ADGRV1 has been previously reported by our laborator y in 2 individuals with hearing loss, one of whom also harbored a second ADGRV1 variant of uncertain significance (trans/cis not yet determined). The variant wa s also identified in 51/126478 European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199499672). However, t his frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Glu32215Lys variant is un certain. ACMG/AMP Criteria applied: PP3. -
Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.75
.;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-0.69
T
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-2.5
.;D
REVEL
Benign
0.19
Sift
Uncertain
0.017
.;D
Sift4G
Uncertain
0.011
.;D
Polyphen
0.84
P;P
Vest4
0.56
MVP
0.73
MPC
0.072
ClinPred
0.35
T
GERP RS
5.8
Varity_R
0.46
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199499672; hg19: chr5-90016771; API