rs371947306

chr5-90828952-G-T

Variant summary

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

The NM_032119.4(ADGRV1):c.16377G>T(p.Gln5459His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,578,762 control chromosomes in the GnomAD database, including 7 homozygotes. 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).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5
• Conservation: PhyloP100: 0.00500

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=0.005907178).
• BP6: Variant 5-90828952-G-T is Benign according to our data. Variant chr5-90828952-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163623.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}. Variant chr5-90828952-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000418 (596/1426682) while in subpopulation SAS AF= 0.00726 (568/78284). AF 95% confidence interval is 0.00676. There are 6 homozygotes in gnomad4_exome. There are 426 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.16377G>T	p.Gln5459His	missense_variant	77/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.16377G>T	p.Gln5459His	missense_variant	77/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 151964 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000953 AC: 232 AN: 243394 Hom.: 2 AF XY: 0.00129 AC XY: 170 AN XY: 132076

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.00773

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000418 AC: 596 AN: 1426682 Hom.: 6 Cov.: 30 AF XY: 0.000603 AC XY: 426 AN XY: 706998

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00726

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.000391

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152080 Hom.: 1 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00747

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000817 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00100 AC: 121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	This variant is associated with the following publications: (PMID: 30245029, 21569298) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ADGRV1: BP4 -

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	- -

Usher syndrome type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

GeneReviews

May 19, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 02, 2015

p.Gln5459His in exon 77 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.7% (120/16090) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org). In addition, the Gln5459 residue is not highly conserved across species, including mammals. Of note, tree shrew has a histidine (His) at this position de spite high nearby amino acid conservation. In addition, computational analyses ( PolyPhen2, SIFT, AlignGVGD) predict that the variant may not impact the protein. The variant has been identified in the heterozygous state in one individual wit h Usher syndrome; however this individual carried a homozygous pathogenic varian t in another gene which explained his clinical manifestations (Bonnet 2011). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	0.17
Dann	Benign	0.83
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
Polyphen		0.0010	B;B;.
Vest4		0.20
MutPred		0.60		Loss of ubiquitination at K5456 (P = 0.0755);Loss of ubiquitination at K5456 (P = 0.0755);.;
MVP		0.072
MPC		0.24
ClinPred		0.079	T
GERP RS		-3.6
Varity_R		0.047
gMVP		0.54

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: rs371947306; hg19: chr5-90124769; COSMIC: COSV101315417;