rs41302842

chr5-90642679-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM5 BP4_Strong BP6_Very_Strong

The NM_032119.4(ADGRV1):c.2284C>T(p.Arg762Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,613,474 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R762H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.122

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-90642680-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.010608077).
• BP6: Variant 5-90642679-C-T is Benign according to our data. Variant chr5-90642679-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90642679-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.2284C>T	p.Arg762Cys	missense_variant	12/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.2284C>T	p.Arg762Cys	missense_variant	12/90	1	NM_032119.4	P1
ADGRV1	ENST00000640403.1	c.-414C>T		5_prime_UTR_variant	2/29	5
ADGRV1	ENST00000504142.2	n.1050C>T		non_coding_transcript_exon_variant	6/14	5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000285 AC: 71 AN: 249012 Hom.: 1 AF XY: 0.000341 AC XY: 46 AN XY: 135088

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000162 AC: 236 AN: 1461292 Hom.: 3 Cov.: 32 AF XY: 0.000201 AC XY: 146 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74390

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000282 AC: 34

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2016

p.Arg762Cys in exon 12 of GPR98: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, >20 species (including >5 mammals) have a cysteine (Cys) at this position despite high nearby amino acid conservation. In addition, computational predicti on tools do not suggest a high likelihood of impact to the protein. It has been identified in 29/16504 (0.2%) of South Asian chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41302842). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.26	T
Polyphen		0.86	P;P
Vest4		0.38
MutPred		0.63		Loss of catalytic residue at R762 (P = 0.121);Loss of catalytic residue at R762 (P = 0.121);
MVP		0.20
MPC		0.060
ClinPred		0.053	T
GERP RS		3.2
Varity_R		0.15
gMVP		0.75

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

Other links and lift over

dbSNP: rs41302842; hg19: chr5-89938496; COSMIC: COSV67996982; COSMIC: COSV67996982;