chr6-152330120-C-G
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_182961.4(SYNE1):c.14565G>C(p.Arg4855Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R4855R) has been classified as Likely benign.
Frequency
Consequence
NM_182961.4 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive ataxia, Beauce typeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
- arthrogryposis multiplex congenita 3, myogenic typeInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Emery-Dreifuss muscular dystrophy 4, autosomal dominantInheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
- autosomal dominant Emery-Dreifuss muscular dystrophyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal recessive myogenic arthrogryposis multiplex congenitaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.14565G>C | p.Arg4855Ser | 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.14565G>C | p.Arg4855Ser | missense_variant | Exon 78 of 146 | 1 | NM_182961.4 | ENSP00000356224.5 | ||
SYNE1 | ENST00000423061.6 | c.14352G>C | p.Arg4784Ser | missense_variant | Exon 77 of 146 | 1 | ENSP00000396024.1 | |||
SYNE1 | ENST00000490135.6 | n.1911G>C | non_coding_transcript_exon_variant | Exon 2 of 11 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727238 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31949146, 32579932) -
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not specified Uncertain:1
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Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 448555). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 4784 of the SYNE1 protein (p.Arg4784Ser). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at