rs79464236

Positions:

• chr5-90791344-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):​c.14515C>G​(p.Gln4839Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00174 in 1,547,346 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. Q4839H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: ADGRV1 NM_032119.4 missense, splice_region
• Scores: Splicing: ADA: 0.9848
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.94

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-90791346-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438169.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008897245).
• BP6: Variant 5-90791344-C-G is Benign according to our data. Variant chr5-90791344-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 46271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90791344-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0022 (335/152272) while in subpopulation EAS AF= 0.0294 (152/5170). AF 95% confidence interval is 0.0256. There are 4 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.14515C>G	p.Gln4839Glu	missense_variant, splice_region_variant	70/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.14515C>G	p.Gln4839Glu	missense_variant, splice_region_variant	70/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00324 AC: 514 AN: 158756 Hom.: 7 AF XY: 0.00313 AC XY: 260 AN XY: 83120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0226

Gnomad SAS exome AF: 0.000612

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00169 AC: 2362 AN: 1395074 Hom.: 51 Cov.: 30 AF XY: 0.00164 AC XY: 1127 AN XY: 687704

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.0000406

Gnomad4 EAS exome AF: 0.0381

Gnomad4 SAS exome AF: 0.000716

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.00155

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74442

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0294

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00134

ExAC AF: 0.00193 AC: 219

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 26969326) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ADGRV1: PM5, BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 23, 2018	- -

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	May 07, 2012	Gln4839Glu in Exon 70 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 4.2% (5/120) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs79 464236). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -

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	0.059
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	.;T;T;T;T
MetaRNN	Benign	0.0064	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	.;N;.;.;.
REVEL	Benign	0.19
Sift	Pathogenic	0.0	.;D;.;.;.
Sift4G	Pathogenic	0.0	.;D;.;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.54
MVP		0.69
MPC		0.084
ClinPred		0.070	T
GERP RS		5.8
Varity_R		0.45
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.010		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: rs79464236; hg19: chr5-90087161; COSMIC: COSV67997853;