NM_032119.4:c.6133G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_032119.4(ADGRV1):​c.6133G>A​(p.Gly2045Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,613,882 control chromosomes in the GnomAD database, including 50 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

Genomes: 𝑓 0.0046 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0065 ( 48 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

8
4
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: 9.69
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 Benign. Variant got -12 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Dann, Eigen, FATHMM_MKL, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.011430383).
BP6
Variant 5-90684054-G-A is Benign according to our data. Variant chr5-90684054-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46348.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=6, Likely_benign=3}. Variant chr5-90684054-G-A is described in Lovd as [Benign]. Variant chr5-90684054-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00461 (702/152222) while in subpopulation NFE AF= 0.00816 (555/68000). AF 95% confidence interval is 0.0076. There are 2 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADGRV1NM_032119.4 linkc.6133G>A p.Gly2045Arg missense_variant Exon 28 of 90 ENST00000405460.9 NP_115495.3 Q8WXG9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADGRV1ENST00000405460.9 linkc.6133G>A p.Gly2045Arg missense_variant Exon 28 of 90 1 NM_032119.4 ENSP00000384582.2 Q8WXG9-1

Frequencies

GnomAD3 genomes
AF:
0.00462
AC:
702
AN:
152104
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00275
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00415
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00816
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00426
AC:
1058
AN:
248490
Hom.:
6
AF XY:
0.00425
AC XY:
573
AN XY:
134858
show subpopulations
Gnomad AFR exome
AF:
0.000775
Gnomad AMR exome
AF:
0.00194
Gnomad ASJ exome
AF:
0.00448
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000752
Gnomad FIN exome
AF:
0.00362
Gnomad NFE exome
AF:
0.00725
Gnomad OTH exome
AF:
0.00315
GnomAD4 exome
AF:
0.00646
AC:
9441
AN:
1461660
Hom.:
48
Cov.:
34
AF XY:
0.00631
AC XY:
4585
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.000896
Gnomad4 AMR exome
AF:
0.00197
Gnomad4 ASJ exome
AF:
0.00413
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000684
Gnomad4 FIN exome
AF:
0.00451
Gnomad4 NFE exome
AF:
0.00772
Gnomad4 OTH exome
AF:
0.00533
GnomAD4 genome
AF:
0.00461
AC:
702
AN:
152222
Hom.:
2
Cov.:
32
AF XY:
0.00437
AC XY:
325
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.00103
Gnomad4 AMR
AF:
0.00275
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00415
Gnomad4 NFE
AF:
0.00816
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00718
Hom.:
7
Bravo
AF:
0.00430
TwinsUK
AF:
0.00593
AC:
22
ALSPAC
AF:
0.00597
AC:
23
ESP6500AA
AF:
0.000273
AC:
1
ESP6500EA
AF:
0.00797
AC:
65
ExAC
AF:
0.00439
AC:
530
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00725
EpiControl
AF:
0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:13
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:8
Feb 25, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24498627, 30245029, 32707200) -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 29, 2018
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 12, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ADGRV1: BS2 -

Jan 31, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:4
May 14, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Gly2045Arg in exon 28 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.7% (480/67628) of European chro mosomes by the Exome Aggregation Consortium, including one homozygote (ExAC, htt p://exac.broadinstitute.org; dbSNP rs41308846). -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 02, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2C Uncertain:1Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Febrile seizures, familial, 4 Uncertain:1
Mar 03, 2014
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T;T;.
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.84
.;T;T
M_CAP
Pathogenic
0.55
D
MetaRNN
Benign
0.011
T;T;T
MetaSVM
Benign
-0.34
T
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-4.4
.;D;.
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0030
.;D;.
Sift4G
Uncertain
0.0050
.;D;.
Polyphen
1.0
D;D;.
Vest4
0.90
MutPred
0.79
Loss of glycosylation at S2044 (P = 0.0283);Loss of glycosylation at S2044 (P = 0.0283);.;
MVP
0.75
MPC
0.35
ClinPred
0.034
T
GERP RS
5.7
Varity_R
0.74
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs41308846; hg19: chr5-89979871; COSMIC: COSV67983965; API