rs876657825

Positions:

• chr5-90651684-G-A
• chr5-90651684-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000405460.9(ADGRV1):​c.3370G>A​(p.Glu1124Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRV1 ENST00000405460.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.3370G>A	p.Glu1124Lys	missense_variant	18/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.3370G>A	p.Glu1124Lys	missense_variant	18/90	1	NM_032119.4	ENSP00000384582	P1
ADGRV1	ENST00000640403.1	c.673G>A	p.Glu225Lys	missense_variant	8/29	5		ENSP00000492531
ADGRV1	ENST00000504142.2	n.2136G>A		non_coding_transcript_exon_variant	12/14	5
ADGRV1	ENST00000639676.1	n.968G>A		non_coding_transcript_exon_variant	6/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 04, 2016

The p.Glu1124Lys variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome and was absent from large population studi es. Computational prediction tools and conservation analysis suggest that this v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu11 24Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	.;N;.
REVEL	Benign	0.25
Sift	Uncertain	0.020	.;D;.
Sift4G	Uncertain	0.010	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.83
MutPred		0.51		Gain of ubiquitination at E1124 (P = 0.0146);Gain of ubiquitination at E1124 (P = 0.0146);.;
MVP		0.63
MPC		0.20
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.45
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs876657825; hg19: chr5-89947501;