rs757366114

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_182961.4(SYNE1):​c.23990C>T​(p.Thr7997Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T7997T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.88
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNE1NM_182961.4 linkc.23990C>T p.Thr7997Met missense_variant Exon 133 of 146 ENST00000367255.10 NP_892006.3
SYNE1NM_001347702.2 linkc.455C>T p.Thr152Met missense_variant Exon 4 of 18 ENST00000354674.5 NP_001334631.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkc.23990C>T p.Thr7997Met missense_variant Exon 133 of 146 1 NM_182961.4 ENSP00000356224.5 Q8NF91-1
SYNE1ENST00000354674.5 linkc.455C>T p.Thr152Met missense_variant Exon 4 of 18 5 NM_001347702.2 ENSP00000346701.4 F8WAI0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251170
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461842
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

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
Sep 13, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine with methionine at codon 7926 of the SYNE1 protein (p.Thr7926Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs757366114, ExAC 0.002%) but has not been reported in the literature in individuals with a SYNE1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.46
T;.;.;T;T;T;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Uncertain
2.8
M;.;.;.;.;.;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.7
D;.;D;D;D;D;D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;.;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.;.
Vest4
0.79
MutPred
0.43
Loss of ubiquitination at K7993 (P = 0.1423);.;.;.;.;.;.;
MVP
0.90
MPC
0.62
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.54
gMVP
0.68

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757366114; hg19: chr6-152476166; COSMIC: COSV54960200; API