rs41302834

chr5-90683751-G-Achr5-90683751-G-T

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.5830G>A(p.Asp1944Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,613,812 control chromosomes in the GnomAD database, including 39 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. D1944Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (34 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.87

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=0.00907135).
• BP6: Variant 5-90683751-G-A is Benign according to our data. Variant chr5-90683751-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90683751-G-A is described in Lovd as [Benign]. Variant chr5-90683751-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00605 (8840/1461642) while in subpopulation NFE AF= 0.00681 (7569/1111838). AF 95% confidence interval is 0.00668. There are 34 homozygotes in gnomad4_exome. There are 4292 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.5830G>A	p.Asp1944Asn	missense_variant	28/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.5830G>A	p.Asp1944Asn	missense_variant	28/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 655 AN: 152050 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00669

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00589

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00433 AC: 1077 AN: 248838 Hom.: 5 AF XY: 0.00425 AC XY: 574 AN XY: 134976

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00605 AC: 8840 AN: 1461642 Hom.: 34 Cov.: 33 AF XY: 0.00590 AC XY: 4292 AN XY: 727098

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00681

Gnomad4 OTH exome AF: 0.00603

GnomAD4 genome AF: 0.00430 AC: 655 AN: 152170 Hom.: 5 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74384

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00668

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00590

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00614 Hom.: 8

Bravo AF: 0.00415

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00724 AC: 60

ExAC AF: 0.00400 AC: 483

EpiCase AF: 0.00643

EpiControl AF: 0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2018	This variant is associated with the following publications: (PMID: 25262649, 21569298, 30245029, 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ADGRV1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	Asp1944Asn in exon 28 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (50/6688) of European American chromosomes in a broad population by the NHLBI Exome sequencing project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs41302834). -

Usher syndrome type 2C Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0091	T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
Polyphen		1.0	D;D;.
Vest4		0.75
MVP		0.75
MPC		0.31
ClinPred		0.019	T
GERP RS		5.7
Varity_R		0.50
gMVP		0.74

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: rs41302834; hg19: chr5-89979568;