rs35092519

chr5-90778942-G-Achr5-90778942-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032119.4(ADGRV1):c.12927G>A(p.Ala4309=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,613,416 control chromosomes in the GnomAD database, including 690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4309A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (123 hom., cov: 32)
  • Exomes 𝑓: 0.024 (567 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.17

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-90778942-G-A is Benign according to our data. Variant chr5-90778942-G-A is described in ClinVar as [Benign]. Clinvar id is 46264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90778942-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.12927G>A	p.Ala4309=	synonymous_variant	64/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.12927G>A	p.Ala4309=	synonymous_variant	64/90	1	NM_032119.4	P1
ADGRV1	ENST00000425867.3	c.1881G>A	p.Ala627=	synonymous_variant	12/38	5
ADGRV1	ENST00000640464.1	n.3346G>A		non_coding_transcript_exon_variant	21/21	5
ADGRV1	ENST00000639431.1	c.265+102733G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5343 AN: 152078 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0379

GnomAD3 exomes AF: 0.0239 AC: 5948 AN: 248854 Hom.: 118 AF XY: 0.0231 AC XY: 3114 AN XY: 134986

Gnomad AFR exome AF: 0.0650

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0771

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00693

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0239 AC: 34922 AN: 1461220 Hom.: 567 Cov.: 31 AF XY: 0.0235 AC XY: 17106 AN XY: 726902

Gnomad4 AFR exome AF: 0.0652

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.0765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00628

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0352 AC: 5351 AN: 152196 Hom.: 123 Cov.: 32 AF XY: 0.0341 AC XY: 2535 AN XY: 74426

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0827

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0375

Alfa AF: 0.0289 Hom.: 38

Bravo AF: 0.0392

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0305

EpiControl AF: 0.0307

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 16, 2010	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2013	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. -

Usher syndrome type 2C Benign:1

Benign, 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 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.046
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs35092519; hg19: chr5-90074759; COSMIC: COSV67996341; COSMIC: COSV67996341;