rs138617999
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_182961.4(SYNE1):c.4822G>A(p.Ala1608Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,960 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SYNE1 | NM_182961.4 | c.4822G>A | p.Ala1608Thr | missense_variant | Exon 37 of 146 | ENST00000367255.10 | NP_892006.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.4822G>A | p.Ala1608Thr | missense_variant | Exon 37 of 146 | 1 | NM_182961.4 | ENSP00000356224.5 | ||
SYNE1 | ENST00000423061.6 | c.4843G>A | p.Ala1615Thr | missense_variant | Exon 37 of 146 | 1 | ENSP00000396024.1 | |||
SYNE1 | ENST00000461872.6 | n.5040G>A | non_coding_transcript_exon_variant | Exon 35 of 55 | 1 | |||||
SYNE1 | ENST00000367253.8 | c.4822G>A | p.Ala1608Thr | missense_variant | Exon 35 of 36 | 5 | ENSP00000356222.4 |
Frequencies
GnomAD3 genomes AF: 0.00103 AC: 156AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000788 AC: 198AN: 251218Hom.: 1 AF XY: 0.000825 AC XY: 112AN XY: 135756
GnomAD4 exome AF: 0.00152 AC: 2224AN: 1461694Hom.: 2 Cov.: 32 AF XY: 0.00143 AC XY: 1041AN XY: 727136
GnomAD4 genome AF: 0.00102 AC: 156AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63AN XY: 74466
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:3
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The SYNE1 c.4843G>A; p.Ala1615Thr variant (rs138617999), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 197018). This variant is found in the non-Finnish European population with an overall allele frequency of 0.15% (195/126496 alleles) in the Genome Aggregation Database. The alanine at codon 1615 is weakly conserved and is found as a threonine in multiple mammalian species, and computational analyses (SIFT: tolerated, PolyPhen-2: benign) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ala1615Thr variant is uncertain at this time. -
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SYNE1: PM2, BP4 -
This variant is associated with the following publications: (PMID: 31692161) -
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not specified Uncertain:1Benign:1
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Variant summary: SYNE1 c.4843G>A (p.Ala1615Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 251218 control chromosomes in the gnomAD database, including 1 homozygote. c.4843G>A has been reported in the literature in at least one individual affected with ataxia without strong evidence for causality (e.g., Ngo_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31692161). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Four laboratories classified the variant as a variant of uncertain significance, three laboratories classified it as likely benign, one laboratory classified it as benign, and one laboratory classified it with conflicting interpretations (VUS/B). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Autosomal recessive ataxia, Beauce type Uncertain:1Benign:1
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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. -
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1615 of the SYNE1 protein (p.Ala1615Thr). This variant is present in population databases (rs138617999, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 31692161). ClinVar contains an entry for this variant (Variation ID: 197018). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Intellectual disability Benign:1
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SYNE1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
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