rs876657824

Positions:

• chr5-90617901-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000405460.9(ADGRV1):​c.305A>G​(p.Asp102Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,180 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 (★). Synonymous variant affecting the same amino acid position (i.e. D102D) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ADGRV1 ENST00000405460.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.40

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.305A>G	p.Asp102Gly	missense_variant	3/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.305A>G	p.Asp102Gly	missense_variant	3/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2016

The p.Asp102Gly variant in GPR98 has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to asses s the frequency of this variant. Computational prediction tools and conservation analysis suggest that the p.Asp102Gly variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp102Gly variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.4	D;.;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.012	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	.;D;D
Vest4		0.77
MutPred		0.66		.;Loss of catalytic residue at D102 (P = 0.0326);Loss of catalytic residue at D102 (P = 0.0326);
MVP		0.77
MPC		0.29
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.63
gMVP		0.77

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: rs876657824; hg19: chr5-89913718;