5-90652488-A-G

Variant names:

• chr5-90652488-A-G
• rs16868935
• NM_032119.4:c.3559A>G

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.3559A>G​(p.Ile1187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,613,458 control chromosomes in the GnomAD database, including 52 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.691
• Publications: 8 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=0.0029987395).
• BP6: Variant 5-90652488-A-G is Benign according to our data. Variant chr5-90652488-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00913 (1391/152296) while in subpopulation AFR AF = 0.0311 (1290/41544). AF 95% confidence interval is 0.0296. There are 25 homozygotes in GnomAd4. There are 673 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR,AD gene

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.3559A>G	p.Ile1187Val	missense	Exon 19 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.3658A>G		non_coding_transcript_exon	Exon 19 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.3559A>G	p.Ile1187Val	missense	Exon 19 of 90	ENSP00000384582.2
	ADGRV1	ENST00000640403.1	TSL:5	c.862A>G	p.Ile288Val	missense	Exon 9 of 29	ENSP00000492531.1
	ADGRV1	ENST00000504142.2	TSL:5	n.2325A>G		non_coding_transcript_exon	Exon 13 of 14

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1392 AN: 152178 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00252 AC: 626 AN: 248896 AF XY: 0.00195

Gnomad AFR exome AF: 0.0307

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00112 AC: 1643 AN: 1461162 Hom.: 27 Cov.: 30 AF XY: 0.000962 AC XY: 699 AN XY: 726842

African (AFR) AF: 0.0331 AC: 1109 AN: 33458

American (AMR) AF: 0.00248 AC: 111 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86188

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53376

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5766

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1111524

Other (OTH) AF: 0.00257 AC: 155 AN: 60348

GnomAD4 genome AF: 0.00913 AC: 1391 AN: 152296 Hom.: 25 Cov.: 32 AF XY: 0.00903 AC XY: 673 AN XY: 74492

African (AFR) AF: 0.0311 AC: 1290 AN: 41544

American (AMR) AF: 0.00444 AC: 68 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68030

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00379 Hom.: 14

Bravo AF: 0.0108

ESP6500AA AF: 0.0286 AC: 108

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00300 AC: 362

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000219

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Mar 26, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ile1187Val in exon 19 of GPR98: This variant is not expected to have clinical significance because it has been identified in 3% (93/3088) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http:// evs.gs.washington.edu/EVS/; dbSNP rs16868935).

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 14, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:5

Feb 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Usher syndrome type 2C Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.0
DANN	Benign	0.40
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.69
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.12
Sift	Benign	0.39	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.073
MVP		0.24
MPC		0.059
ClinPred		0.0029	T
GERP RS		-7.0
Varity_R		0.025
gMVP		0.38
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs16868935; hg19: chr5-89948305; COSMIC: COSV99072956;