rs13171868

Positions:

• chr5-90745757-T-C

Variant summary

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

The ENST00000405460.9(ADGRV1):​c.10936T>C​(p.Ser3646Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,611,356 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (33 hom.)
• Consequence: ADGRV1 ENST00000405460.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.336

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=0.009298831).
• BP6: Variant 5-90745757-T-C is Benign according to our data. Variant chr5-90745757-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163597.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=2, Uncertain_significance=1}. Variant chr5-90745757-T-C is described in Lovd as [Likely_benign]. Variant chr5-90745757-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00625 (9126/1459052) while in subpopulation NFE AF= 0.0073 (8105/1110222). AF 95% confidence interval is 0.00717. There are 33 homozygotes in gnomad4_exome. There are 4363 alleles in male gnomad4_exome subpopulation. Median coverage is 29. 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	Protein	UniProt
ADGRV1	NM_032119.4	c.10936T>C	p.Ser3646Pro	missense_variant	52/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.10936T>C	p.Ser3646Pro	missense_variant	52/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152186 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00444 AC: 1102 AN: 248116 Hom.: 5 AF XY: 0.00434 AC XY: 584 AN XY: 134646

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.00675

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00625 AC: 9126 AN: 1459052 Hom.: 33 Cov.: 29 AF XY: 0.00601 AC XY: 4363 AN XY: 725986

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00440

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.00730

Gnomad4 OTH exome AF: 0.00496

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152304 Hom.: 4 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74474

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00584 Hom.: 7

Bravo AF: 0.00343

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00160 AC: 6

ESP6500EA AF: 0.00657 AC: 54

ExAC AF: 0.00438 AC: 529

EpiCase AF: 0.00529

EpiControl AF: 0.00563

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2018	This variant is associated with the following publications: (PMID: 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ADGRV1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser3646Pro in Exon 52 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (47/6622) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs13171868). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 19, 2020	- -

Usher syndrome type 2C Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.68	.;T;T
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.55	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	.;N;.
REVEL	Benign	0.057
Sift	Benign	0.19	.;T;.
Sift4G	Uncertain	0.023	.;D;.
Polyphen		0.79	P;P;.
Vest4		0.16
MVP		0.37
MPC		0.057
ClinPred		0.015	T
GERP RS		1.7
Varity_R		0.29
gMVP		0.55

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: rs13171868; hg19: chr5-90041574;