rs372484022

Positions:

• chr5-90720066-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032119.4(ADGRV1):​c.9466A>G​(p.Ile3156Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,676 control chromosomes in the GnomAD database, including 2 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 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0880

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058565736).
• BP6: Variant 5-90720066-A-G is Benign according to our data. Variant chr5-90720066-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46405.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.9466A>G	p.Ile3156Val	missense_variant	44/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.9466A>G	p.Ile3156Val	missense_variant	44/90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000274 AC: 68 AN: 247736 Hom.: 1 AF XY: 0.000349 AC XY: 47 AN XY: 134564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1461314 Hom.: 2 Cov.: 31 AF XY: 0.000209 AC XY: 152 AN XY: 726946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74516

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000356 AC: 43

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2019	This variant is associated with the following publications: (PMID: 29266188) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ADGRV1 p.Ile3156Val variant was identified in 1 of 190 proband chromosomes (frequency: 0.00526) from individuals or families with myoclonic seizures and was not identified in 1056 control chromosomes from healthy individuals (Myers_2018_PMID:29266188). The variant was also identified in dbSNP (ID: rs372484022) and in ClinVar (classifed as a VUS by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 69 of 279132 chromosomes (1 homozygous) at a frequency of 0.000247 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 57 of 30568 chromosomes (freq: 0.001865), Latino in 3 of 35298 chromosomes (freq: 0.000085), European (non-Finnish) in 7 of 127064 chromosomes (freq: 0.000055), African in 1 of 24196 chromosomes (freq: 0.000041), European (Finnish) in 1 of 25022 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, East Asian, and Other populations. The p.Ile3156 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Variant classified as Uncertain Significance - Favor Benign. The Ile3156Val vari ant (GPR98) has not been reported in the literature or in SNP databases nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein; however, Isoleucine (Ile) a t position 3156 is replaced by Val (Valine) in zebrafish suggesting the variant is more likely benign. In summary, the clinical significance of this variant can not be determined with certainty at this time, though we would lean towards a mo re likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.8
DANN	Benign	0.91
DEOGEN2	Benign	0.046	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.60	.;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.17	.;N
REVEL	Benign	0.035
Sift	Benign	0.54	.;T
Sift4G	Benign	0.26	.;T
Polyphen		0.27	B;B
Vest4		0.24
MutPred		0.33		Loss of stability (P = 0.1311);Loss of stability (P = 0.1311);
MVP		0.24
MPC		0.12
ClinPred		0.035	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs372484022; hg19: chr5-90015883;