rs201388114

chr5-90675427-C-Gchr5-90675427-C-T

Variant summary

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

The NM_032119.4(ADGRV1):c.5295C>G(p.Phe1765Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,613,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 1.26

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=0.0855737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.5295C>G	p.Phe1765Leu	missense_variant	24/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.5295C>G	p.Phe1765Leu	missense_variant	24/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000603

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000250 AC: 62 AN: 248158 Hom.: 0 AF XY: 0.000238 AC XY: 32 AN XY: 134572

Gnomad AFR exome AF: 0.000130

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: 0.000515

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000611 AC: 892 AN: 1461086 Hom.: 0 Cov.: 31 AF XY: 0.000612 AC XY: 445 AN XY: 726762

Gnomad4 AFR exome AF: 0.0000896

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: 0.000746

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74356

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000482 AC: 4

ExAC AF: 0.000215 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADGRV1: PM2:Supporting, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 16, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 24, 2017	The p.Phe1765Leu variant in GPR98 has not been previously reported in individual s with hearing loss, but has been identified in 58/126298 European chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; db SNP rs201388114). Computational prediction tools and conservation analysis sugge st that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of the p.Phe1765Leu variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.5295C>G (p.F1765L) alteration is located in exon 24 (coding exon 24) of the ADGRV1 gene. This alteration results from a C to G substitution at nucleotide position 5295, causing the phenylalanine (F) at amino acid position 1765 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	15
Dann	Uncertain	0.97
DEOGEN2	Benign	0.078	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	D
PrimateAI	Benign	0.32	T
Polyphen		0.069	B;B;.
Vest4		0.48
MutPred		0.38		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.34
MPC		0.055
ClinPred		0.026	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201388114; hg19: chr5-89971244; COSMIC: COSV105343876; COSMIC: COSV105343876;