rs4645434

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182961.4(SYNE1):c.12180G>T(p.Glu4060Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,613,888 control chromosomes in the GnomAD database, including 292,794 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24306 hom., cov: 32)

Exomes 𝑓: 0.60 ( 268488 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.394

Publications

48 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive ataxia, Beauce type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
arthrogryposis multiplex congenita 3, myogenic type
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Emery-Dreifuss muscular dystrophy 4, autosomal dominant
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
autosomal dominant Emery-Dreifuss muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive myogenic arthrogryposis multiplex congenita
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SYNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2501399E-5).

BP6

Variant 6-152344126-C-A is Benign according to our data. Variant chr6-152344126-C-A is described in ClinVar as Benign. ClinVar VariationId is 130397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.12180G>T	p.Glu4060Asp	missense_variant	Exon 74 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 link	c.12180G>T	p.Glu4060Asp	missense_variant	Exon 74 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.11967G>T	p.Glu3989Asp	missense_variant	Exon 73 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000471834.1 link	n.5318G>T		non_coding_transcript_exon_variant	Exon 17 of 19	1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

85068

AN:

151952

Hom.:

24292

Cov.:

show subpopulations

Gnomad AFR

AF:

0.449

Gnomad AMI

AF:

0.569

Gnomad AMR

AF:

0.604

Gnomad ASJ

AF:

0.650

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.528

Gnomad FIN

AF:

0.534

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.580

GnomAD2 exomes

AF:

0.583

AC:

146655

AN:

251458

AF XY:

0.582

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.600

Gnomad ASJ exome

AF:

0.653

Gnomad EAS exome

AF:

0.639

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.608

Gnomad OTH exome

AF:

0.589

GnomAD4 exome

AF:

0.604

AC:

883635

AN:

1461816

Hom.:

268488

Cov.:

AF XY:

0.602

AC XY:

437602

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.439

AC:

14691

AN:

33478

American (AMR)

AF:

0.601

AC:

26893

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.657

AC:

17172

AN:

26134

East Asian (EAS)

AF:

0.645

AC:

25606

AN:

39696

South Asian (SAS)

AF:

0.514

AC:

44339

AN:

86258

European-Finnish (FIN)

AF:

0.546

AC:

29177

AN:

53406

Middle Eastern (MID)

AF:

0.522

AC:

3009

AN:

5764

European-Non Finnish (NFE)

AF:

0.618

AC:

686712

AN:

1111964

Other (OTH)

AF:

0.597

AC:

36036

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

21449

42898

64348

85797

107246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18524

37048

55572

74096

92620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.560

AC:

85124

AN:

152072

Hom.:

24306

Cov.:

AF XY:

0.556

AC XY:

41303

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.449

AC:

18618

AN:

41462

American (AMR)

AF:

0.605

AC:

9252

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.650

AC:

2252

AN:

3466

East Asian (EAS)

AF:

0.640

AC:

3302

AN:

5156

South Asian (SAS)

AF:

0.527

AC:

2543

AN:

4830

European-Finnish (FIN)

AF:

0.534

AC:

5637

AN:

10564

Middle Eastern (MID)

AF:

0.503

AC:

148

AN:

294

European-Non Finnish (NFE)

AF:

0.612

AC:

41624

AN:

67988

Other (OTH)

AF:

0.582

AC:

1230

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1929

3858

5786

7715

9644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.598

Hom.:

135593

Bravo

AF:

0.562

TwinsUK

AF:

0.608

AC:

2255

ALSPAC

AF:

0.629

AC:

2423

ESP6500AA

AF:

0.469

AC:

2065

ESP6500EA

AF:

0.618

AC:

5313

ExAC

AF:

0.576

AC:

69938

Asia WGS

AF:

0.593

AC:

2064

AN:

3478

EpiCase

AF:

0.602

EpiControl

AF:

0.597

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Nov 02, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arthrogryposis multiplex congenita 3, myogenic type

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.9

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.11

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.48

T;T;T

MetaRNN

Benign

0.000013

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

N;.;.

PhyloP100

0.39

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

N;.;N

REVEL

Benign

0.058

Sift

Benign

0.071

T;.;T

Sift4G

Uncertain

0.042

D;T;D

Polyphen

0.20

B;.;.

Vest4

0.13

MutPred

0.089

Loss of helix (P = 0.028);.;.;

MPC

0.13

ClinPred

0.0067

GERP RS

-1.3

Varity_R

0.054

gMVP

0.088

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over