rs761667882

chr5-90784004-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032119.4(ADGRV1):c.13600A>G(p.Met4534Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.817

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039669454).
• BP6: Variant 5-90784004-A-G is Benign according to our data. Variant chr5-90784004-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505538.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.13600A>G	p.Met4534Val	missense_variant	67/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.13600A>G	p.Met4534Val	missense_variant	67/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247460 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134222

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460690 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726552

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 28, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Met4534Val va riant in GPR98 has not been previously reported in individuals with hearing loss , but has been identified in 1/8888 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs761667882). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conserv ation analysis suggest that the p.Met4534Val variant may not impact the protein. Of note, the methionine (Met) at position 4534 is not conserved through species , with 1 mammal (goat) having a valine (Val). In summary, while the clinical sig nificance of the p.Met4534Val variant is uncertain, its presence in other specie s suggests that it is more likely to be benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.76
DEOGEN2	Benign	0.082	T;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
Polyphen		0.0030	B;B;.;.
Vest4		0.14
MutPred		0.40		Loss of disorder (P = 0.1402);Loss of disorder (P = 0.1402);.;.;
MVP		0.21
MPC		0.091
ClinPred		0.023	T
GERP RS		2.0
Varity_R		0.045
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs761667882; hg19: chr5-90079821;