rs200512504

chr5-90689929-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_032119.4(ADGRV1):c.6559A>G(p.Ile2187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,613,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2187M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.05

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0086914).
• BP6: Variant 5-90689929-A-G is Benign according to our data. Variant chr5-90689929-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179159.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=2}. Variant chr5-90689929-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000414 (63/152286) while in subpopulation EAS AF= 0.0114 (59/5186). AF 95% confidence interval is 0.00905. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.6559A>G	p.Ile2187Val	missense_variant	30/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.6559A>G	p.Ile2187Val	missense_variant	30/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00104 AC: 258 AN: 247752 Hom.: 0 AF XY: 0.000990 AC XY: 133 AN XY: 134348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0142

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000244 AC: 356 AN: 1460914 Hom.: 0 Cov.: 30 AF XY: 0.000237 AC XY: 172 AN XY: 726678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00834

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152286 Hom.: 0 Cov.: 31 AF XY: 0.000430 AC XY: 32 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000579 Hom.: 1

Bravo AF: 0.000514

ExAC AF: 0.000927 AC: 112

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 2C Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2020	This variant is associated with the following publications: (PMID: 23767834, 30245029) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 18, 2018	The p.Ile2187Val variant (rs200512504) has been previously reported as a homozygote in a Chinese patient included in a cohort of non-syndromic hearing loss patients (Yang 2013). The variant was also identified in deaf relatives, and no other significant variants were identified in 78 other deafness-associated genes. However, this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in East Asians of 1.4% (identified in 270 out of 18,802 chromosomes). Additionally, isoleucine and valine have similar physiochemical properties (Alamut software v2.9), and species of hare, rodent, and fish have a valine at codon 2187 suggesting this change is evolutionary tolerated. This variant is also not predicted to influence ADGRV1 mRNA splicing (Alamut software v2.9), and is listed in the ClinVar database as likely benign (Variation ID: 179159). Therefore, the p.Ile2187Val variant is likely to be benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2013

Ile2187Val in exon 30 of GPR98: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, guinea pig, rabbit, tenrec, stickleback, medaka, and lamprey have a valine (Val) at this position despite high nearby amino acid conservation. In addition, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likel ihood of impact to the protein. Furthermore, this variant has been identified in 1% (2/200) of Han Chinese chromosomes by the 1000 Genomes Project (dbSNP rs2005 12504). This variant has been reported in the literature homozygous in one indiv idual with hearing loss (Yang 2013); however, this individual is reported to be of Han Chinese ancestry, which is consistent with a higher frequency of this var iant in that population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.075	T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
Polyphen		0.058	B;B;.
Vest4		0.15
MVP		0.27
MPC		0.11
ClinPred		0.050	T
GERP RS		1.6
Varity_R		0.078
gMVP		0.37

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: rs200512504; hg19: chr5-89985746; COSMIC: COSV67990137; COSMIC: COSV67990137;