5-90724960-C-T

Variant names:

• chr5-90724960-C-T
• rs769215629
• NM_032119.4:c.9877C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032119.4(ADGRV1):​c.9877C>T​(p.Arg3293*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,450,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.98

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]

LOC105379077 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-90724960-C-T is Pathogenic according to our data. Variant chr5-90724960-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90724960-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.9877C>T	p.Arg3293*	stop_gained	Exon 46 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.9877C>T	p.Arg3293*	stop_gained	Exon 46 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000830 AC: 2 AN: 240904 Hom.: 0 AF XY: 0.00000766 AC XY: 1 AN XY: 130496

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000575

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1450694 Hom.: 0 Cov.: 29 AF XY: 0.0000153 AC XY: 11 AN XY: 721172

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000242

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg3293*) in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADGRV1 are known to be pathogenic (PMID: 19357117, 22135276, 22147658, 26226137, 30718709, 31047384, 32467589). This variant is present in population databases (rs769215629, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome (PMID: 27460420). ClinVar contains an entry for this variant (Variation ID: 517415). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32037395, 27460420) -

Usher syndrome type 2C Pathogenic:1

Apr 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9877C>T;p.(Arg3293*) variant creates a premature translational stop signal in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 517415; PMID: 27460420) - PS4. The variant is present at low allele frequencies population databases (rs769215629 – gnomAD 0.00008302%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg3293*) was detected in trans with a pathogenic variant (PMID: 27460420) - PM3_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Rare genetic deafness Pathogenic:1

Jul 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg3293X variant in GPR98 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 1/109096 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org/; dbSNP rs769215629). This nonsense variant leads to a premature term ination codon at position 3293, which is predicted to lead to a truncated or abs ent protein. Loss of function of the GPR98 gene is an established disease mechan ism in autosomal recessive Usher syndrome type 2. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome type 2 in an autosom al recessive manner based on predicted impact to the protein. -

Retinal dystrophy Pathogenic:1

Dec 05, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.052
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs769215629; hg19: chr5-90020777;