rs73181648

chr5-90653530-G-Achr5-90653530-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):c.3956G>A(p.Arg1319Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000608 in 1,613,868 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1319W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.64

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=0.008273959).
• BP6: Variant 5-90653530-G-A is Benign according to our data. Variant chr5-90653530-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90653530-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00349 (531/152234) while in subpopulation AFR AF= 0.0125 (519/41536). AF 95% confidence interval is 0.0116. There are 4 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.3956G>A	p.Arg1319Gln	missense_variant	20/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.3956G>A	p.Arg1319Gln	missense_variant	20/90	1	NM_032119.4	P1
ADGRV1	ENST00000640403.1	c.1247G>A	p.Arg416Gln	missense_variant	10/29	5
ADGRV1	ENST00000504142.2	n.2722G>A		non_coding_transcript_exon_variant	14/14	5
ADGRV1	ENST00000639676.1	n.1554G>A		non_coding_transcript_exon_variant	8/11	5

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 533 AN: 152116 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000840 AC: 209 AN: 248940 Hom.: 2 AF XY: 0.000607 AC XY: 82 AN XY: 135040

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461634 Hom.: 4 Cov.: 32 AF XY: 0.000260 AC XY: 189 AN XY: 727090

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152234 Hom.: 4 Cov.: 32 AF XY: 0.00343 AC XY: 255 AN XY: 74428

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000453 Hom.: 1

Bravo AF: 0.00390

ESP6500AA AF: 0.0110 AC: 43

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2020	This variant is associated with the following publications: (PMID: 30180840) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Arg1319Gln in Exon 20 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (36/3232) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs73181648). -

Usher syndrome type 2C Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
Polyphen		1.0	D;D;.
Vest4		0.56
MVP		0.67
MPC		0.20
ClinPred		0.033	T
GERP RS		5.4
Varity_R		0.24
gMVP		0.80

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: rs73181648; hg19: chr5-89949347; COSMIC: COSV101315866; COSMIC: COSV101315866;