rs563408259
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_182961.4(SYNE1):c.22589+4G>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
SYNE1
NM_182961.4 splice_donor_region, intron
NM_182961.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00003496
2
Clinical Significance
Conservation
PhyloP100: 0.309
Genes affected
SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.22589+4G>T | splice_donor_region_variant, intron_variant | ENST00000367255.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.22589+4G>T | splice_donor_region_variant, intron_variant | 1 | NM_182961.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250986Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135642
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459086Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726070
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74408
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2022 | This sequence change falls in intron 123 of the SYNE1 gene. It does not directly change the encoded amino acid sequence of the SYNE1 protein. It affects a nucleotide within the consensus splice site. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 538423). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs563408259, gnomAD 0.003%). - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
Find out detailed SpliceAI scores and Pangolin per-transcript scores at