rs199761238

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_182961.4(SYNE1):ā€‹c.13768A>Gā€‹(p.Asn4590Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,613,990 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N4590S) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00017 ( 0 hom., cov: 32)
Exomes š‘“: 0.00040 ( 1 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

1
6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 8.02
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 Likely_benign. Variant got -6 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=0.19585338).
BP6
Variant 6-152330917-T-C is Benign according to our data. Variant chr6-152330917-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282206.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.
BS2
High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SYNE1NM_182961.4 linkuse as main transcriptc.13768A>G p.Asn4590Asp 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.13768A>G p.Asn4590Asp missense_variant 78/1461 NM_182961.4 ENSP00000356224.5 Q8NF91-1
SYNE1ENST00000423061.6 linkuse as main transcriptc.13555A>G p.Asn4519Asp missense_variant 77/1461 ENSP00000396024.1 A0A0C4DG40
SYNE1ENST00000490135.6 linkuse as main transcriptn.1114A>G non_coding_transcript_exon_variant 2/111

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
41
AN:
251326
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.0000618
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000325
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000400
AC:
584
AN:
1461794
Hom.:
1
Cov.:
82
AF XY:
0.000355
AC XY:
258
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000507
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000484
Hom.:
0
Bravo
AF:
0.000219
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.000436
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:7
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024SYNE1: PM2:Supporting -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 24, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 26, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsMay 08, 2023Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 31, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27378695, 29892087, 29961767) -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 4519 of the SYNE1 protein (p.Asn4519Asp). This variant is present in population databases (rs199761238, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 282206). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Autosomal recessive ataxia, Beauce type Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 30, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.29
T;.;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.2
M;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-2.1
N;.;N
REVEL
Benign
0.11
Sift
Benign
0.30
T;.;T
Sift4G
Benign
0.14
T;T;T
Polyphen
0.82
P;.;.
Vest4
0.45
MVP
0.33
MPC
0.60
ClinPred
0.12
T
GERP RS
5.9
Varity_R
0.27
gMVP
0.11

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: rs199761238; hg19: chr6-152652052; API