rs142388112
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_182961.4(SYNE1):c.13909G>A(p.Asp4637Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,858 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_182961.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.13909G>A | p.Asp4637Asn | missense_variant | Exon 78 of 146 | ENST00000367255.10 | NP_892006.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.13909G>A | p.Asp4637Asn | missense_variant | Exon 78 of 146 | 1 | NM_182961.4 | ENSP00000356224.5 | ||
SYNE1 | ENST00000423061.6 | c.13696G>A | p.Asp4566Asn | missense_variant | Exon 77 of 146 | 1 | ENSP00000396024.1 | |||
SYNE1 | ENST00000490135.6 | n.1255G>A | non_coding_transcript_exon_variant | Exon 2 of 11 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00104 AC: 158AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000793 AC: 199AN: 250802Hom.: 1 AF XY: 0.000812 AC XY: 110AN XY: 135544
GnomAD4 exome AF: 0.00133 AC: 1941AN: 1461586Hom.: 4 Cov.: 33 AF XY: 0.00129 AC XY: 935AN XY: 727100
GnomAD4 genome AF: 0.00104 AC: 158AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62AN XY: 74446
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
This variant is associated with the following publications: (PMID: 31692161) -
- -
not specified Benign:2
- -
- -
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 4566 of the SYNE1 protein (p.Asp4566Asn). This variant is present in population databases (rs142388112, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pure cerebellar ataxia (PMID: 31692161). ClinVar contains an entry for this variant (Variation ID: 282531). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Autosomal recessive ataxia, Beauce type Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at