rs214976

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.3104T>C(p.Val1035Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,613,752 control chromosomes in the GnomAD database, including 167,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 22767 hom., cov: 31)

Exomes 𝑓: 0.44 ( 144873 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 8.64

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=5.3290587E-6).

BP6

Variant 6-152451129-A-G is Benign according to our data. Variant chr6-152451129-A-G is described in ClinVar as Benign. ClinVar VariationId is 130438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.3104T>C	p.Val1035Ala	missense_variant	Exon 26 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 link	c.3104T>C	p.Val1035Ala	missense_variant	Exon 26 of 146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.524

AC:

79540

AN:

151822

Hom.:

22727

Cov.:

show subpopulations

Gnomad AFR

AF:

0.746

Gnomad AMI

AF:

0.281

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.495

Gnomad EAS

AF:

0.758

Gnomad SAS

AF:

0.540

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.418

Gnomad OTH

AF:

0.530

GnomAD2 exomes

AF:

0.469

AC:

117956

AN:

251420

AF XY:

0.470

show subpopulations

Gnomad AFR exome

AF:

0.754

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.487

Gnomad EAS exome

AF:

0.764

Gnomad FIN exome

AF:

0.400

Gnomad NFE exome

AF:

0.423

Gnomad OTH exome

AF:

0.446

GnomAD4 exome

AF:

0.436

AC:

637374

AN:

1461814

Hom.:

144873

Cov.:

AF XY:

0.439

AC XY:

319127

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.756

AC:

25312

AN:

33480

American (AMR)

AF:

0.339

AC:

15161

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.484

AC:

12649

AN:

26136

East Asian (EAS)

AF:

0.779

AC:

30909

AN:

39700

South Asian (SAS)

AF:

0.522

AC:

45010

AN:

86254

European-Finnish (FIN)

AF:

0.395

AC:

21118

AN:

53404

Middle Eastern (MID)

AF:

0.512

AC:

2953

AN:

5768

European-Non Finnish (NFE)

AF:

0.410

AC:

455860

AN:

1111958

Other (OTH)

AF:

0.470

AC:

28402

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

20224

40449

60673

80898

101122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14254

28508

42762

57016

71270

<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:

0.524

AC:

79634

AN:

151938

Hom.:

22767

Cov.:

AF XY:

0.522

AC XY:

38758

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.747

AC:

30956

AN:

41460

American (AMR)

AF:

0.423

AC:

6452

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.495

AC:

1716

AN:

3464

East Asian (EAS)

AF:

0.759

AC:

3911

AN:

5156

South Asian (SAS)

AF:

0.540

AC:

2598

AN:

4812

European-Finnish (FIN)

AF:

0.386

AC:

4066

AN:

10526

Middle Eastern (MID)

AF:

0.514

AC:

150

AN:

292

European-Non Finnish (NFE)

AF:

0.418

AC:

28413

AN:

67950

Other (OTH)

AF:

0.530

AC:

1116

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1749

3498

5246

6995

8744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.453

Hom.:

74963

Bravo

AF:

0.536

TwinsUK

AF:

0.408

AC:

1512

ALSPAC

AF:

0.403

AC:

1552

ESP6500AA

AF:

0.734

AC:

3232

ESP6500EA

AF:

0.430

AC:

3694

ExAC

AF:

0.481

AC:

58402

Asia WGS

AF:

0.628

AC:

2186

AN:

3478

EpiCase

AF:

0.432

EpiControl

AF:

0.429

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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. -

Jan 25, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:3

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. -

May 28, 2019

Mendelics

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

- -

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

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;T;.;.;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D;D;D;D

MetaRNN

Benign

0.0000053

T;T;T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.9

L;.;.;L;.;L

PhyloP100

8.6

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.4

N;.;N;D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0060

D;.;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Polyphen

0.0090

B;.;.;B;B;.

Vest4

0.38

MPC

0.23

ClinPred

0.048

GERP RS

5.8

Varity_R

0.17

gMVP

0.39

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

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

Publications

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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