rs10067636

chr5-90725218-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.10039T>C(p.Phe3347Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,461,344 control chromosomes in the GnomAD database, including 146 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 0.019 (84 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (62 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.313

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]

LOC105379077 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014689565).
• BP6: Variant 5-90725218-T-C is Benign according to our data. Variant chr5-90725218-T-C is described in ClinVar as [Benign]. Clinvar id is 46244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90725218-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.10039T>C	p.Phe3347Leu	missense_variant	47/90	ENST00000405460.9
LOC105379077	XR_001742802.2	n.364-9409A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.10039T>C	p.Phe3347Leu	missense_variant	47/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2954 AN: 152146 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00548 AC: 783 AN: 142846 Hom.: 23 AF XY: 0.00427 AC XY: 338 AN XY: 79216

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000223

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.00165 AC: 2158 AN: 1309080 Hom.: 62 Cov.: 23 AF XY: 0.00147 AC XY: 954 AN XY: 650622

Gnomad4 AFR exome AF: 0.0622

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.0194 AC: 2959 AN: 152264 Hom.: 84 Cov.: 33 AF XY: 0.0186 AC XY: 1382 AN XY: 74466

Gnomad4 AFR AF: 0.0677

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00986 Hom.: 20

Bravo AF: 0.0217

ESP6500AA AF: 0.0623 AC: 222

ESP6500EA AF: 0.000250 AC: 2

ExAC AF: 0.00531 AC: 629

Asia WGS AF: 0.00407 AC: 14 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2013	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	Eurofins Ntd Llc (ga)	Jun 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Phe3347Leu in Exon 47 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 5.8% (166/2862) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs10067636). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 2C Benign:1

Benign, 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 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	0.48
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	14
Dann	Benign	0.55
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.040	N
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.35	T
Polyphen		0.0	B;B
Vest4		0.061
MutPred		0.30		Loss of methylation at K3348 (P = 0.0285);Loss of methylation at K3348 (P = 0.0285);
MVP		0.10
MPC		0.053
ClinPred		0.0025	T
GERP RS		0.88
Varity_R		0.056
gMVP		0.38

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: rs10067636; hg19: chr5-90021035;