5-90652372-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_032119.4(ADGRV1):​c.3443G>T​(p.Gly1148Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,603,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1148D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

9
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.72
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 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-90652372-G-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADGRV1NM_032119.4 linkc.3443G>T p.Gly1148Val missense_variant Exon 19 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.3443G>T p.Gly1148Val missense_variant Exon 19 of 90 1 NM_032119.4 ENSP00000384582.2 Q8WXG9-1
ADGRV1ENST00000640403.1 linkc.746G>T p.Gly249Val missense_variant Exon 9 of 29 5 ENSP00000492531.1 A0A1W2PRC7
ADGRV1ENST00000504142.2 linkn.2209G>T non_coding_transcript_exon_variant Exon 13 of 14 5
ADGRV1ENST00000639676.1 linkn.1041G>T non_coding_transcript_exon_variant Exon 7 of 11 5

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1451346
Hom.:
0
Cov.:
31
AF XY:
0.00000139
AC XY:
1
AN XY:
720832
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000181
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Feb 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1148 of the ADGRV1 protein (p.Gly1148Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1350508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADGRV1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
T;T;.
Eigen
Uncertain
0.64
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.82
.;T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Uncertain
-0.098
T
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-6.2
.;D;.
REVEL
Uncertain
0.57
Sift
Pathogenic
0.0
.;D;.
Sift4G
Pathogenic
0.0
.;D;.
Polyphen
1.0
D;D;.
Vest4
0.95
MutPred
0.62
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;
MVP
0.74
MPC
0.34
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.93
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.27
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.27
Position offset: 23

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: rs200945405; hg19: chr5-89948189; API