rs182395524

Positions:

• chr5-90642944-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032119.4(ADGRV1):​c.2456G>A​(p.Ser819Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.33

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043358207).
• BP6: Variant 5-90642944-G-A is Benign according to our data. Variant chr5-90642944-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158650.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.2456G>A	p.Ser819Asn	missense_variant	13/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.2456G>A	p.Ser819Asn	missense_variant	13/90	1	NM_032119.4	ENSP00000384582.2
ADGRV1	ENST00000640403	c.-242G>A		5_prime_UTR_variant	3/29	5		ENSP00000492531.1
ADGRV1	ENST00000504142.2	n.1222G>A		non_coding_transcript_exon_variant	7/14	5
ADGRV1	ENST00000639676.1	n.54G>A		non_coding_transcript_exon_variant	1/11	5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000607 AC: 151 AN: 248742 Hom.: 0 AF XY: 0.000459 AC XY: 62 AN XY: 134936

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00418

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461296 Hom.: 1 Cov.: 32 AF XY: 0.0000949 AC XY: 69 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74422

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000518 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000546 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 24, 2017	The p.Ser819Asn variant (rs182395524) has not been previously associated with hearing loss and is listed in the ClinVar database as likely benign or as a variant of uncertain significance (Variation ID: 158650). This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Latino populations of 0.428% (identified in 147 out of 34,382 chromosomes). The serine at codon 819 is highly conserved (Alamut software v2.9); however, avian species have an asparagine at this position suggesting this change is evolutionary tolerated. Furthermore, due to similar physiochemical properties between serine and asparagine, computational analyses suggest this variant does not have a significant effect on ADGRV1 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism).Thus, the p.Ser819Asn variant is likely to be benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2018	p.Ser819Asn in exon 13 of ADGRV1: This variant is classified as likely benign du e to a lack of conservation across species, including mammals. Of note, rabbit h as an asparagine at this position despite nearby amino acid conservation. In add ition, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has been identified in 0.4% (147/34382) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs182395524). ACMG/AMP Criteria applied: BS1_Supporting, BP4 -

Febrile seizures, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 27, 2013

- -

ADGRV1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2020

This variant is classified as likely 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	0.098
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.28	.;N
REVEL	Benign	0.045
Sift	Benign	0.26	.;T
Sift4G	Benign	0.42	.;T
Polyphen		0.0040	B;B
Vest4		0.21
MVP		0.36
MPC		0.14
ClinPred		0.0095	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.46

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: rs182395524; hg19: chr5-89938761;