rs111033530

chr5-90705420-G-Achr5-90705420-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.8407G>A(p.Ala2803Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,613,454 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 32)
  • Exomes 𝑓: 0.016 (222 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.30

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=0.007953525).
• BP6: Variant 5-90705420-G-A is Benign according to our data. Variant chr5-90705420-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90705420-G-A is described in Lovd as [Benign]. Variant chr5-90705420-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0108 (1639/152246) while in subpopulation NFE AF= 0.0181 (1233/68008). AF 95% confidence interval is 0.0173. There are 15 homozygotes in gnomad4. There are 734 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.8407G>A	p.Ala2803Thr	missense_variant	37/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.8407G>A	p.Ala2803Thr	missense_variant	37/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1639 AN: 152128 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.0107 AC: 2670 AN: 248650 Hom.: 19 AF XY: 0.0110 AC XY: 1478 AN XY: 134842

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.00580

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0161 AC: 23573 AN: 1461208 Hom.: 222 Cov.: 31 AF XY: 0.0158 AC XY: 11450 AN XY: 726854

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00620

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0108 AC: 1639 AN: 152246 Hom.: 15 Cov.: 32 AF XY: 0.00986 AC XY: 734 AN XY: 74426

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0148 Hom.: 31

Bravo AF: 0.0101

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00382 AC: 15

ESP6500EA AF: 0.0162 AC: 135

ExAC AF: 0.0104 AC: 1259

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0156

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 20, 2012	Ala2803Thr in exon 37 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 1.66% (112/6714) of European Americ an chromosomes and 0.43% (14/3234) of African American chromosomes by the NHLBI Exome sequencing project in a broad population in a broad population (http://evs .gs.washington.edu/EVS, rs111033530, http://evidence.personalgenomes.org/GPR98-A 2803T). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -

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. -

ADGRV1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
Polyphen		1.0	D;D;.
Vest4		0.78
MPC		0.31
ClinPred		0.017	T
GERP RS		5.8
Varity_R		0.51
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs111033530; hg19: chr5-90001237;