NM_032119.4:c.12631C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_032119.4(ADGRV1):​c.12631C>T​(p.Arg4211*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 1,439,158 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.259

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 5-90778008-C-T is Pathogenic according to our data. Variant chr5-90778008-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 179305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADGRV1NM_032119.4 linkc.12631C>T p.Arg4211* stop_gained Exon 62 of 90 ENST00000405460.9 NP_115495.3 Q8WXG9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADGRV1ENST00000405460.9 linkc.12631C>T p.Arg4211* stop_gained Exon 62 of 90 1 NM_032119.4 ENSP00000384582.2 Q8WXG9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000953
AC:
2
AN:
209970
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000110
Gnomad OTH exome
AF:
0.000189
GnomAD4 exome
AF:
0.00000556
AC:
8
AN:
1439158
Hom.:
0
Cov.:
31
AF XY:
0.00000701
AC XY:
5
AN XY:
713612
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33200
American (AMR)
AF:
0.00
AC:
0
AN:
41054
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25578
East Asian (EAS)
AF:
0.0000256
AC:
1
AN:
39138
South Asian (SAS)
AF:
0.0000120
AC:
1
AN:
83168
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52276
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
0.00000364
AC:
4
AN:
1099446
Other (OTH)
AF:
0.0000336
AC:
2
AN:
59558
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000830
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Dec 17, 2023
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.Arg4211*) 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 (rs727504777, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 33724713). ClinVar contains an entry for this variant (Variation ID: 179305). 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. -

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Pathogenic:1
Apr 30, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Rare genetic deafness Pathogenic:1
Oct 11, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Arg4211X variant in GPR98 has not been reported in individuals with hearing loss or in large population studies. This nonsense variant leads to a premature termination codon at position 4211, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Benign
0.30
N
PhyloP100
0.26
Vest4
0.24
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs727504777; hg19: chr5-90073825; COSMIC: COSV67990775; COSMIC: COSV67990775; API