5-90811291-A-G

Variant names:

• chr5-90811291-A-G
• rs2438374
• NM_032119.4:c.16031A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):​c.16031A>G​(p.Glu5344Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,612,382 control chromosomes in the GnomAD database, including 759,533 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E5344E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.94 (67407 hom., cov: 33)
  • Exomes 𝑓: 0.97 (692126 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.71
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.7724985E-7).
• BP6: Variant 5-90811291-A-G is Benign according to our data. Variant chr5-90811291-A-G is described in ClinVar as Benign. ClinVar VariationId is 46282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.16031A>G	p.Glu5344Gly	missense	Exon 74 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.16047A>G		non_coding_transcript_exon	Exon 74 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.16031A>G	p.Glu5344Gly	missense	Exon 74 of 90	ENSP00000384582.2
	ADGRV1	ENST00000638510.1	TSL:1	n.3298A>G		non_coding_transcript_exon	Exon 10 of 26
	ADGRV1	ENST00000425867.3	TSL:5	c.4985A>G	p.Glu1662Gly	missense	Exon 22 of 38	ENSP00000392618.3

Frequencies

GnomAD3 genomes AF: 0.939 AC: 142915 AN: 152140 Hom.: 67375 Cov.: 33

Gnomad AFR AF: 0.847

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.982

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.976

Gnomad OTH AF: 0.936

GnomAD2 exomes AF: 0.970 AC: 238719 AN: 246210 AF XY: 0.972

Gnomad AFR exome AF: 0.846

Gnomad AMR exome AF: 0.980

Gnomad ASJ exome AF: 0.923

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.981

Gnomad NFE exome AF: 0.974

Gnomad OTH exome AF: 0.969

GnomAD4 exome AF: 0.973 AC: 1421241 AN: 1460124 Hom.: 692126 Cov.: 39 AF XY: 0.974 AC XY: 707375 AN XY: 726148

African (AFR) AF: 0.843 AC: 28195 AN: 33436

American (AMR) AF: 0.977 AC: 43516 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.923 AC: 24079 AN: 26076

East Asian (EAS) AF: 1.00 AC: 39694 AN: 39694

South Asian (SAS) AF: 0.994 AC: 85183 AN: 85732

European-Finnish (FIN) AF: 0.982 AC: 52412 AN: 53384

Middle Eastern (MID) AF: 0.960 AC: 5531 AN: 5760

European-Non Finnish (NFE) AF: 0.976 AC: 1084415 AN: 1111150

Other (OTH) AF: 0.965 AC: 58216 AN: 60336

GnomAD4 genome AF: 0.939 AC: 143001 AN: 152258 Hom.: 67407 Cov.: 33 AF XY: 0.941 AC XY: 70051 AN XY: 74464

African (AFR) AF: 0.847 AC: 35146 AN: 41512

American (AMR) AF: 0.962 AC: 14714 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3184 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5181 AN: 5182

South Asian (SAS) AF: 0.993 AC: 4796 AN: 4828

European-Finnish (FIN) AF: 0.982 AC: 10424 AN: 10618

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.976 AC: 66382 AN: 68036

Other (OTH) AF: 0.937 AC: 1982 AN: 2116

Alfa AF: 0.959 Hom.: 159013

Bravo AF: 0.932

TwinsUK AF: 0.971 AC: 3599

ALSPAC AF: 0.975 AC: 3758

ESP6500AA AF: 0.854 AC: 3209

ESP6500EA AF: 0.973 AC: 8017

ExAC AF: 0.968 AC: 116947

Asia WGS AF: 0.987 AC: 3433 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Caucasian frequency = 6466/6644 (ESP data)

Mar 06, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 2C Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Benign	0.24
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.036	T
MetaRNN	Benign	7.8e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.053
ClinPred		0.0024	T
GERP RS		4.6
Varity_R		0.060
gMVP		0.52
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2438374; hg19: chr5-90107108; COSMIC: COSV108245833; COSMIC: COSV108245833;