rs119103243
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_182961.4(SYNE1):c.8695A>T(p.Arg2899*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,984 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
Consequence
NM_182961.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.8695A>T | p.Arg2899* | stop_gained | Exon 56 of 146 | ENST00000367255.10 | NP_892006.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000282 AC: 7AN: 248530Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134560
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461744Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727190
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with ataxia with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant appears to segregate with disease in at least one family. This variant is also referred to as R2906X in published literature. -
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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27178001, 17159980, 30275942, 23959263, 33397523) -
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Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg2906*) in the SYNE1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNE1 are known to be pathogenic (PMID: 19542096, 24319099, 27086870). This variant is present in population databases (rs119103243, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with autosomal recessive spinocerebellar ataxia (PMID: 17159980). ClinVar contains an entry for this variant (Variation ID: 2327). For these reasons, this variant has been classified as Pathogenic. -
Autosomal recessive ataxia, Beauce type Pathogenic:1
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Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at