rs371947306

Variant names:

• chr5-90828952-G-T
• rs371947306
• NM_032119.4:c.16377G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• 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

Our verdict: Benign. The variant received -20 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 [Likely_benign]. Clinvar id is 163623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90828952-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00027 (41/152080) while in subpopulation SAS AF = 0.00747 (36/4818). AF 95% confidence interval is 0.00555. There are 1 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.16377G>T	p.Gln5459His	missense_variant	Exon 77 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.16377G>T	p.Gln5459His	missense_variant	Exon 77 of 90	1	NM_032119.4	ENSP00000384582.2

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

GnomAD2 exomes AF: 0.000953 AC: 232 AN: 243394 AF XY: 0.00129

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 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 AC: 1 AN: 32992

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 43654

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25156

Gnomad4 EAS exome AF: 0.0000254 AC: 1 AN: 39348

Gnomad4 SAS exome AF: 0.00726 AC: 568 AN: 78284

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51904

Gnomad4 NFE exome AF: 0.00000183 AC: 2 AN: 1090918

Gnomad4 Remaining exome AF: 0.000391 AC: 23 AN: 58808

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 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00747 AC: 0.00747198 AN: 0.00747198

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588426 AN: 0.0000588426

Gnomad4 OTH AF: 0.000475 AC: 0.000474834 AN: 0.000474834

Alfa AF: 0.000108 Hom.: 1

Bravo AF: 0.0000416

ExAC AF: 0.00100 AC: 121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 21, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30245029, 21569298) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADGRV1: BP4 -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2C Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2025

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Pathogenic:1

May 19, 2016

GeneReviews

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

not specified Benign:1

Mar 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Benign	0.53	.;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	.;N;.
REVEL	Benign	0.21
Sift	Benign	0.053	.;T;.
Sift4G	Uncertain	0.0040	.;D;.
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
Mutation Taster		=78/22	polymorphism

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;