rs62000408

chr5-90789837-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):c.14029T>C(p.Phe4677Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,446,920 control chromosomes in the GnomAD database, including 636 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (331 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (305 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012586713).
• BP6: Variant 5-90789837-T-C is Benign according to our data. Variant chr5-90789837-T-C is described in ClinVar as [Benign]. Clinvar id is 46269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90789837-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.14029T>C	p.Phe4677Leu	missense_variant	69/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.14029T>C	p.Phe4677Leu	missense_variant	69/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5326 AN: 152144 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0100 AC: 1334 AN: 132946 Hom.: 75 AF XY: 0.00781 AC XY: 553 AN XY: 70834

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.00790

Gnomad ASJ exome AF: 0.00389

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000368

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00368 AC: 4764 AN: 1294658 Hom.: 305 Cov.: 29 AF XY: 0.00334 AC XY: 2108 AN XY: 631158

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.00815

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000346

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00882

GnomAD4 genome AF: 0.0351 AC: 5343 AN: 152262 Hom.: 331 Cov.: 32 AF XY: 0.0338 AC XY: 2516 AN XY: 74452

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00646 Hom.: 90

Bravo AF: 0.0405

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.111 AC: 398

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.00873 AC: 999

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 25, 2013	This variant is not expected to have clinical significance because it is has bee n identified in 11% (317/2884) of African American chromosomes from a broad popu lation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs62000408). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -

Usher syndrome type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	16
Dann	Benign	0.37
DEOGEN2	Benign	0.078	T;T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.19	N
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
Polyphen		0.0	B;B;.;.
Vest4		0.039
MutPred		0.38		Loss of methylation at K4674 (P = 0.1816);Loss of methylation at K4674 (P = 0.1816);.;.;
MPC		0.071
ClinPred		0.0042	T
GERP RS		-0.57
Varity_R		0.056
gMVP		0.35

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: rs62000408; hg19: chr5-90085654;