rs1554111603

Positions:

• chr5-90774232-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000405460.9(ADGRV1):​c.12332T>C​(p.Val4111Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADGRV1 ENST00000405460.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.45

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12888062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.12332T>C	p.Val4111Ala	missense_variant	60/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.12332T>C	p.Val4111Ala	missense_variant	60/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 04, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Val4111Ala va riant in GPR98 has not been previously reported in individuals with hearing loss or Usher syndrome, or in large population databases. The valine (Val) at posit ion 4111 is not conserved across species including mammals. Of note, two mammals (naked mole rat, rabbit) have an alanine (Ala) at this position despite high ne arby amino acid sequence conservation, suggesting that the change at this positi on may be tolerated. Additional computational prediction tools suggest that thi s variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Val4111Ala variant is uncertain, the conservation data suggest that it is more likely to be benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 505267). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4111 of the ADGRV1 protein (p.Val4111Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.2
DANN	Benign	0.58
DEOGEN2	Benign	0.087	T;T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.38	.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	.;N;.
REVEL	Benign	0.050
Sift	Benign	0.17	.;T;.
Sift4G	Benign	0.44	.;T;.
Polyphen		0.0020	B;B;.
Vest4		0.13
MutPred		0.57		Loss of stability (P = 0.021);Loss of stability (P = 0.021);.;
MVP		0.15
MPC		0.055
ClinPred		0.035	T
GERP RS		-1.2
Varity_R		0.080
gMVP		0.45

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: rs1554111603; hg19: chr5-90070049;