rs199839743

chr5-90763453-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032119.4(ADGRV1):c.12269C>A(p.Thr4090Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,612,340 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T4090T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (28 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.03

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016502231).
• BP6: Variant 5-90763453-C-A is Benign according to our data. Variant chr5-90763453-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46259.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=4}. Variant chr5-90763453-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00572 (8348/1460152) while in subpopulation NFE AF= 0.00719 (7983/1110614). AF 95% confidence interval is 0.00706. There are 28 homozygotes in gnomad4_exome. There are 4020 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.12269C>A	p.Thr4090Asn	missense_variant	59/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.12269C>A	p.Thr4090Asn	missense_variant	59/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 534 AN: 152070 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00164

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: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00287 AC: 714 AN: 249016 Hom.: 1 AF XY: 0.00295 AC XY: 399 AN XY: 135120

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00572 AC: 8348 AN: 1460152 Hom.: 28 Cov.: 32 AF XY: 0.00554 AC XY: 4020 AN XY: 726116

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00719

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00351 AC: 534 AN: 152188 Hom.: 3 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74414

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00666

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00535 Hom.: 2

Bravo AF: 0.00320

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00135 AC: 5

ESP6500EA AF: 0.00561 AC: 46

ExAC AF: 0.00245 AC: 296

EpiCase AF: 0.00487

EpiControl AF: 0.00564

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ADGRV1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 26969326, 30180840, 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Thr4090Asn in Exon 59 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (39/6606) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2015	- -

Usher syndrome type 2C Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ADGRV1-related condition 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	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.36	T
Polyphen		1.0	D;D;.
Vest4		0.87
MVP		0.68
MPC		0.32
ClinPred		0.019	T
GERP RS		4.3
Varity_R		0.38
gMVP		0.69

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: rs199839743; hg19: chr5-90059270; COSMIC: COSV67993205; COSMIC: COSV67993205;