rs77469944

Positions:

• chr5-91150072-A-G

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.18475A>G​(p.Met6159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,552,142 control chromosomes in the GnomAD database, including 1,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (366 hom., cov: 30)
  • Exomes 𝑓: 0.012 (742 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.41

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017308891).
• BP6: Variant 5-91150072-A-G is Benign according to our data. Variant chr5-91150072-A-G is described in ClinVar as [Benign]. Clinvar id is 46298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-91150072-A-G is described in Lovd as [Benign]. Variant chr5-91150072-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.18475A>G	p.Met6159Val	missense_variant	88/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.18475A>G	p.Met6159Val	missense_variant	88/90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6329 AN: 150442 Hom.: 364 Cov.: 30

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00578

Gnomad EAS AF: 0.0444

Gnomad SAS AF: 0.0800

Gnomad FIN AF: 0.00158

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.0309

GnomAD3 exomes AF: 0.0265 AC: 4328 AN: 163388 Hom.: 222 AF XY: 0.0288 AC XY: 2478 AN XY: 86066

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.00840

Gnomad ASJ exome AF: 0.00511

Gnomad EAS exome AF: 0.0447

Gnomad SAS exome AF: 0.0924

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0119 AC: 16652 AN: 1401586 Hom.: 742 Cov.: 34 AF XY: 0.0138 AC XY: 9526 AN XY: 691652

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00529

Gnomad4 EAS exome AF: 0.0275

Gnomad4 SAS exome AF: 0.0862

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0422 AC: 6354 AN: 150556 Hom.: 366 Cov.: 30 AF XY: 0.0418 AC XY: 3069 AN XY: 73378

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.00578

Gnomad4 EAS AF: 0.0443

Gnomad4 SAS AF: 0.0807

Gnomad4 FIN AF: 0.00158

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.0306

Alfa AF: 0.0117 Hom.: 130

Bravo AF: 0.0469

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.119 AC: 445

ESP6500EA AF: 0.00208 AC: 17

ExAC AF: 0.0213 AC: 2440

Asia WGS AF: 0.0620 AC: 214 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 27, 2012	Met6159Val in exon 88 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 11% (347/3046) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http: //evs.gs.washington.edu/EVS/; dbSNP rs77469944). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2015	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)	May 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

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	Benign	0.084
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T;T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.72	.;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.51	.;N;.;.
REVEL	Benign	0.099
Sift	Benign	0.057	.;T;.;.
Sift4G	Uncertain	0.030	.;D;.;.
Polyphen		0.0	B;B;.;.
Vest4		0.21
MPC		0.048
ClinPred		0.014	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.27

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: rs77469944; hg19: chr5-90445889;