rs373780305
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_032119.4(ADGRV1):c.2398C>T(p.Arg800Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000023 in 1,607,408 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: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
ADGRV1
NM_032119.4 stop_gained
NM_032119.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.61
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]
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ACMG classification
Classification made for transcript
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 5-90642886-C-T is Pathogenic according to our data. Variant chr5-90642886-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 46306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90642886-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADGRV1 | NM_032119.4 | c.2398C>T | p.Arg800Ter | stop_gained | 13/90 | ENST00000405460.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADGRV1 | ENST00000405460.9 | c.2398C>T | p.Arg800Ter | stop_gained | 13/90 | 1 | NM_032119.4 | P1 | |
ADGRV1 | ENST00000640403.1 | c.-300C>T | 5_prime_UTR_variant | 3/29 | 5 | ||||
ADGRV1 | ENST00000504142.2 | n.1164C>T | non_coding_transcript_exon_variant | 7/14 | 5 | ||||
ADGRV1 | ENST00000639676.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000329 AC: 8AN: 243508Hom.: 0 AF XY: 0.0000378 AC XY: 5AN XY: 132116
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GnomAD4 exome AF: 0.0000234 AC: 34AN: 1455344Hom.: 0 Cov.: 33 AF XY: 0.0000249 AC XY: 18AN XY: 723578
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2022 | Nonsense variant predicted to result in 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: 22135276, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change creates a premature translational stop signal (p.Arg800*) 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 (rs373780305, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 22135276). ClinVar contains an entry for this variant (Variation ID: 46306). 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
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2013 | The Arg800X variant in GPR98 has been reported in one individual with Usher synd rome who had a second GPR98 variant (Le Quesne Stabej 2012). This nonsense varia nt leads to a premature termination codon at position 800, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our crite ria to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
0.29
ClinPred
D
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at