rs183319660

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000405460.9(ADGRV1):​c.10768A>T​(p.Ser3590Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,567,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000067 ( 2 hom. )

Consequence

ADGRV1
ENST00000405460.9 missense, splice_region

Scores

5
13
Splicing: ADA: 0.9784
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.50
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03485784).
BS2
High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADGRV1NM_032119.4 linkuse as main transcriptc.10768A>T p.Ser3590Cys missense_variant, splice_region_variant 51/90 ENST00000405460.9 NP_115495.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADGRV1ENST00000405460.9 linkuse as main transcriptc.10768A>T p.Ser3590Cys missense_variant, splice_region_variant 51/901 NM_032119.4 ENSP00000384582 P1Q8WXG9-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
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
GnomAD3 exomes
AF:
0.000227
AC:
51
AN:
224386
Hom.:
1
AF XY:
0.000229
AC XY:
28
AN XY:
122326
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00125
Gnomad ASJ exome
AF:
0.00102
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000281
Gnomad OTH exome
AF:
0.000370
GnomAD4 exome
AF:
0.0000671
AC:
95
AN:
1415644
Hom.:
2
Cov.:
25
AF XY:
0.0000712
AC XY:
50
AN XY:
702498
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00116
Gnomad4 ASJ exome
AF:
0.000844
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000174
Gnomad4 OTH exome
AF:
0.000136
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152284
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000980
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
Alfa
AF:
0.0000906
Hom.:
0
Bravo
AF:
0.000219
ExAC
AF:
0.000157
AC:
19

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 25, 2022This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3590 of the ADGRV1 protein (p.Ser3590Cys). This variant is present in population databases (rs183319660, gnomAD 0.1%). 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: 505525). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Likely benign, criteria provided, single submitterclinical testingGeneDxAug 18, 2020This variant is associated with the following publications: (PMID: 27460420) -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 28, 2020The ADGRV1 c.10768A>T; p.Ser3590Cys variant (rs183319660) is reported in the literature in an individual affected with Usher syndrome who also carried a homozygous MYO7A variant (Bonnet 2016). This variant is reported in ClinVar (Variation ID: 505525), and is found in the Latino population with an allele frequency of 0.12% (38/30556 alleles, including a single homozygote) in the Genome Aggregation Database. The serine at codon 3590 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, however without functional studies, the effect on splicing is unknown. Due to limited information, the clinical significance of the p.Ser3590Cys variant is uncertain at this time. References: Bonnet et al. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. Eur J Hum Genet. 2016 Dec;24(12):1730-1738. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 13, 2016The p.Ser3590Cys variant in GPR98 has been previously reported in 1 individual w ith type 1 Usher syndrome explained by a homozygous variant in another gene (Bon net 2016). The p.Ser3590Cys variant has been reported in 0.1% (36/31300) of Lat ino chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs183319660). Computational prediction tools and conserva tion analyses suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. Furthermore, this variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not suggest an impact to splicing. However , this information is not predictive enough to rule out pathogenicity. In summar y, the clinical significance of the p.Ser3590Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T;T
Eigen
Benign
0.064
Eigen_PC
Benign
-0.0058
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.84
.;T
M_CAP
Uncertain
0.099
D
MetaRNN
Benign
0.035
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-3.1
.;D
REVEL
Benign
0.15
Sift
Benign
0.043
.;D
Sift4G
Uncertain
0.0040
.;D
Polyphen
1.0
D;D
Vest4
0.54
MVP
0.59
MPC
0.32
ClinPred
0.22
T
GERP RS
3.1
Varity_R
0.24
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Benign
0.68
SpliceAI score (max)
0.040
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: rs183319660; hg19: chr5-90041081; API