rs6880570

Variant names:

• chr5-90705551-T-G
• rs6880570
• NM_032119.4:c.8538T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_032119.4(ADGRV1):​c.8538T>G​(p.Leu2846Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,612,200 control chromosomes in the GnomAD database, including 21,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3815 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17453 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.48
• Publications: 19 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.236).
• BP6: Variant 5-90705551-T-G is Benign according to our data. Variant chr5-90705551-T-G is described in ClinVar as Benign. ClinVar VariationId is 46390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.8538T>G	p.Leu2846Leu	synonymous_variant	Exon 37 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.8538T>G	p.Leu2846Leu	synonymous_variant	Exon 37 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30743 AN: 151998 Hom.: 3796 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.180 AC: 44738 AN: 248916 AF XY: 0.176

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.409

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.142 AC: 207202 AN: 1460084 Hom.: 17453 Cov.: 32 AF XY: 0.143 AC XY: 104105 AN XY: 726348

African (AFR) AF: 0.345 AC: 11530 AN: 33426

American (AMR) AF: 0.146 AC: 6538 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 5462 AN: 26114

East Asian (EAS) AF: 0.372 AC: 14765 AN: 39680

South Asian (SAS) AF: 0.197 AC: 16937 AN: 86162

European-Finnish (FIN) AF: 0.163 AC: 8697 AN: 53386

Middle Eastern (MID) AF: 0.176 AC: 1007 AN: 5732

European-Non Finnish (NFE) AF: 0.119 AC: 131904 AN: 1110550

Other (OTH) AF: 0.172 AC: 10362 AN: 60324

GnomAD4 genome AF: 0.202 AC: 30797 AN: 152116 Hom.: 3815 Cov.: 32 AF XY: 0.205 AC XY: 15274 AN XY: 74394

African (AFR) AF: 0.333 AC: 13809 AN: 41462

American (AMR) AF: 0.160 AC: 2452 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3468

East Asian (EAS) AF: 0.405 AC: 2092 AN: 5166

South Asian (SAS) AF: 0.202 AC: 974 AN: 4822

European-Finnish (FIN) AF: 0.162 AC: 1714 AN: 10592

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8458 AN: 68006

Other (OTH) AF: 0.210 AC: 442 AN: 2108

Alfa AF: 0.153 Hom.: 7208

Bravo AF: 0.210

Asia WGS AF: 0.335 AC: 1163 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.131

ClinVar

Significance: Benign

Submissions summary: Benign:9

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

- -

Jan 08, 2013

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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 19, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2C Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.0
DANN	Benign	0.84
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6880570; hg19: chr5-90001368; COSMIC: COSV67978733;