rs140927945
Positions:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_182961.4(SYNE1):c.9655G>A(p.Val3219Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000211 in 1,613,214 control chromosomes in the GnomAD database, including 1 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
Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
SYNE1
NM_182961.4 missense
NM_182961.4 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 3.82
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 Benign. Variant got -8 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SYNE1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.009579062).
BP6
?
Variant 6-152369124-C-T is Benign according to our data. Variant chr6-152369124-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290182.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}.
BS2
?
High AC in GnomAd4 at 183 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.9655G>A | p.Val3219Ile | missense_variant | 61/146 | ENST00000367255.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.9655G>A | p.Val3219Ile | missense_variant | 61/146 | 1 | NM_182961.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00120 AC: 183AN: 152178Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000244 AC: 61AN: 250120Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135164
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GnomAD4 exome AF: 0.000108 AC: 158AN: 1460918Hom.: 0 Cov.: 30 AF XY: 0.0000826 AC XY: 60AN XY: 726818
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GnomAD4 genome ? AF: 0.00120 AC: 183AN: 152296Hom.: 1 Cov.: 32 AF XY: 0.00126 AC XY: 94AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2018 | A variant of uncertain significance has been identified in the SYNE1 gene. The V3226I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V3226I variant is observed in 34/10238 (0.3%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V3226I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 19, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 21, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | SYNE1: BS1 - |
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
SYNE1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 05, 2019 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;.
REVEL
Benign
Sift
Uncertain
D;.;D;.
Sift4G
Benign
T;T;T;T
Polyphen
P;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at