rs796051865
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000405460.9(ADGRV1):βc.18732_18750delβ(p.Tyr6244Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000992 in 1,612,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000033 ( 0 hom., cov: 32)
Exomes π: 0.0000075 ( 0 hom. )
Consequence
ADGRV1
ENST00000405460.9 frameshift
ENST00000405460.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.02
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]
LUCAT1 (HGNC:48498): (lung cancer associated transcript 1)
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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 5-91153323-GGATATGGCCAGGGGTCACT-G is Pathogenic according to our data. Variant chr5-91153323-GGATATGGCCAGGGGTCACT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-91153323-GGATATGGCCAGGGGTCACT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ADGRV1 | NM_032119.4 | c.18732_18750del | p.Tyr6244Ter | frameshift_variant | 89/90 | ENST00000405460.9 | NP_115495.3 | |
| LOC107986432 | XR_001742795.2 | n.1208-1154_1208-1136del | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ADGRV1 | ENST00000405460.9 | c.18732_18750del | p.Tyr6244Ter | frameshift_variant | 89/90 | 1 | NM_032119.4 | ENSP00000384582 | P1 | |
| LUCAT1 | ENST00000650150.1 | n.380-1154_380-1136del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000810 AC: 2AN: 247032Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134010
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460452Hom.: 0 AF XY: 0.00000551 AC XY: 4AN XY: 726372
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GnomAD4 genome 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Tyr6244*) 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 (rs761560344, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 14740321). ClinVar contains an entry for this variant (Variation ID: 6801). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2024 | Observed in four siblings with clinical features of Usher syndrome type 2, however a second variant in ADGRV1 was not identified (PMID: 14740321); Nonsense variant predicted to result in protein truncation, as the last 63 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14740321) - |
Usher syndrome type 2C Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2004 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at