rs141141950

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_182961.4(SYNE1):​c.14091G>T​(p.Met4697Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,613,672 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

1
18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.69
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.
BP4
Computational evidence support a benign effect (MetaRNN=0.006858647).
BP6
Variant 6-152330594-C-A is Benign according to our data. Variant chr6-152330594-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 284031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 343 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SYNE1NM_182961.4 linkuse as main transcriptc.14091G>T p.Met4697Ile missense_variant 78/146 ENST00000367255.10 NP_892006.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkuse as main transcriptc.14091G>T p.Met4697Ile missense_variant 78/1461 NM_182961.4 ENSP00000356224.5 Q8NF91-1
SYNE1ENST00000423061.6 linkuse as main transcriptc.13878G>T p.Met4626Ile missense_variant 77/1461 ENSP00000396024.1 A0A0C4DG40
SYNE1ENST00000490135.6 linkuse as main transcriptn.1437G>T non_coding_transcript_exon_variant 2/111

Frequencies

GnomAD3 genomes
AF:
0.00224
AC:
341
AN:
152170
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00811
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000456
AC:
114
AN:
249746
Hom.:
1
AF XY:
0.000363
AC XY:
49
AN XY:
135146
show subpopulations
Gnomad AFR exome
AF:
0.00660
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.000266
AC:
389
AN:
1461384
Hom.:
0
Cov.:
32
AF XY:
0.000209
AC XY:
152
AN XY:
727022
show subpopulations
Gnomad4 AFR exome
AF:
0.00908
Gnomad4 AMR exome
AF:
0.0000447
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:
0.0000441
Gnomad4 OTH exome
AF:
0.000480
GnomAD4 genome
AF:
0.00225
AC:
343
AN:
152288
Hom.:
1
Cov.:
32
AF XY:
0.00220
AC XY:
164
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00813
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000180
Hom.:
1
Bravo
AF:
0.00257
ESP6500AA
AF:
0.00613
AC:
27
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000478
AC:
58
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 11, 2015- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 04, 2020- -
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 10, 2021This variant is associated with the following publications: (PMID: 28017257) -
Autosomal recessive ataxia, Beauce type Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
SYNE1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 12, 2021This 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
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
17
DANN
Benign
0.56
DEOGEN2
Benign
0.13
T;.;T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.044
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.78
T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.0069
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;.;.
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.1
N;.;N
REVEL
Benign
0.059
Sift
Benign
0.068
T;.;T
Sift4G
Benign
0.15
T;T;T
Polyphen
0.017
B;.;.
Vest4
0.44
MutPred
0.36
Loss of phosphorylation at T4702 (P = 0.0813);.;.;
MVP
0.46
MPC
0.15
ClinPred
0.0066
T
GERP RS
5.9
Varity_R
0.45
gMVP
0.21

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: rs141141950; hg19: chr6-152651729; COSMIC: COSV54975656; COSMIC: COSV54975656; API