rs200140440

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_182961.4(SYNE1):c.12829G>A(p.Ala4277Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,613,432 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.12

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]

SYNE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10811657).

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.12829G>A	p.Ala4277Thr	missense_variant	Exon 78 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 link	c.12829G>A	p.Ala4277Thr	missense_variant	Exon 78 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.12616G>A	p.Ala4206Thr	missense_variant	Exon 77 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000490135.6 link	n.175G>A		non_coding_transcript_exon_variant	Exon 2 of 11	1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250602

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461076

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00139

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Uncertain:1

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 579339). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs200140440, gnomAD 0.06%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4206 of the SYNE1 protein (p.Ala4206Thr). -

not provided

Uncertain:1

Feb 07, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.16

Sift

Benign

0.033

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.43

MVP

0.45

MPC

0.34

ClinPred

0.45

GERP RS

4.6

Varity_R

0.17

gMVP

0.071

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over