rs41308846

chr5-90684054-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_032119.4(ADGRV1):c.6133G>A(p.Gly2045Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,613,882 control chromosomes in the GnomAD database, including 50 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 0.0046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (48 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 9.69

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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Dann, Eigen, FATHMM_MKL, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011430383).
• BP6: Variant 5-90684054-G-A is Benign according to our data. Variant chr5-90684054-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46348.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=2, Uncertain_significance=2}. Variant chr5-90684054-G-A is described in Lovd as [Benign]. Variant chr5-90684054-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00461 (702/152222) while in subpopulation NFE AF= 0.00816 (555/68000). AF 95% confidence interval is 0.0076. There are 2 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.6133G>A	p.Gly2045Arg	missense_variant	28/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.6133G>A	p.Gly2045Arg	missense_variant	28/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 702 AN: 152104 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00426 AC: 1058 AN: 248490 Hom.: 6 AF XY: 0.00425 AC XY: 573 AN XY: 134858

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00448

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00362

Gnomad NFE exome AF: 0.00725

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00646 AC: 9441 AN: 1461660 Hom.: 48 Cov.: 34 AF XY: 0.00631 AC XY: 4585 AN XY: 727106

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.00451

Gnomad4 NFE exome AF: 0.00772

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00437 AC XY: 325 AN XY: 74428

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.00816

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00718 Hom.: 7

Bravo AF: 0.00430

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000273 AC: 1

ESP6500EA AF: 0.00797 AC: 65

ExAC AF: 0.00439 AC: 530

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	This variant is associated with the following publications: (PMID: 24498627, 30245029, 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 31, 2017	- -
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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADGRV1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2015	p.Gly2045Arg in exon 28 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.7% (480/67628) of European chro mosomes by the Exome Aggregation Consortium, including one homozygote (ExAC, htt p://exac.broadinstitute.org; dbSNP rs41308846). -

Usher syndrome type 2C Uncertain:1 Benign: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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Febrile seizures, familial, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 03, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.79		Loss of glycosylation at S2044 (P = 0.0283);Loss of glycosylation at S2044 (P = 0.0283);.;
MVP		0.75
MPC		0.35
ClinPred		0.034	T
GERP RS		5.7
Varity_R		0.74
gMVP		0.76

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: rs41308846; hg19: chr5-89979871; COSMIC: COSV67983965;