chr5-90684054-G-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:1B:14

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: {Likely_benign=3, Benign=6, Uncertain_significance=2}. 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:1Benign:14
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:8
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

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

- -

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

- -

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

ADGRV1: BS2 -

Mar 29, 2018
Athena Diagnostics
Significance: Likely 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

- -

not specified Benign:4
-
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

- -

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). -

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

- -

Usher syndrome type 2C Benign:2
May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 08, 2025
Illumina Laboratory Services, Illumina
Significance: Likely 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