chr5-90674226-A-G

Variant names:

• chr5-90674226-A-G
• rs876657826
• NM_032119.4:c.5102A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_032119.4(ADGRV1):​c.5102A>G​(p.His1701Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000555 in 1,442,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.94
• Publications: 0 publications found

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]

ADGRV1 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.5102A>G	p.His1701Arg	missense_variant	Exon 23 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.5102A>G	p.His1701Arg	missense_variant	Exon 23 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000555 AC: 8 AN: 1442736 Hom.: 0 Cov.: 30 AF XY: 0.00000559 AC XY: 4 AN XY: 715998

African (AFR) AF: 0.00 AC: 0 AN: 32974

American (AMR) AF: 0.00 AC: 0 AN: 42520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.00 AC: 0 AN: 81390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52804

Middle Eastern (MID) AF: 0.000880 AC: 5 AN: 5680

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102912

Other (OTH) AF: 0.0000168 AC: 1 AN: 59626

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.His1701Arg variant in GPR98 has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analyses do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.His1701Arg va riant is uncertain. -

not provided Uncertain:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1701 of the ADGRV1 protein (p.His1701Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228722). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.99	T
PhyloP100		8.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	.;D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.015	.;D;.
Sift4G	Uncertain	0.014	.;D;.
Polyphen		0.94	P;P;.
Vest4		0.66
MutPred		0.20		Gain of phosphorylation at S1699 (P = 0.0877);Gain of phosphorylation at S1699 (P = 0.0877);.;
MVP		0.72
MPC		0.29
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.55
gMVP		0.71
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs876657826; hg19: chr5-89970043;