6-152326546-A-T

Variant names:

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.15043T>A(p.Leu5015Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,614,054 control chromosomes in the GnomAD database, including 476,515 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L5015L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.81 ( 50926 hom., cov: 33)

Exomes 𝑓: 0.76 ( 425589 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.93

Publications

44 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=5.5081324E-7).

BP6

Variant 6-152326546-A-T is Benign according to our data. Variant chr6-152326546-A-T is described in ClinVar as Benign. ClinVar VariationId is 130408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.15043T>A	p.Leu5015Met	missense_variant	Exon 79 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYNE1	ENST00000367255.10 link	c.15043T>A	p.Leu5015Met	missense_variant	Exon 79 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6 link	c.14830T>A	p.Leu4944Met	missense_variant	Exon 78 of 146	1		ENSP00000396024.1
SYNE1	ENST00000490135.6 link	n.2389T>A		non_coding_transcript_exon_variant	Exon 3 of 11	1

Frequencies

GnomAD3 genomes

AF:

0.814

AC:

123789

AN:

152076

Hom.:

50859

Cov.:

show subpopulations

Gnomad AFR

AF:

0.932

Gnomad AMI

AF:

0.720

Gnomad AMR

AF:

0.819

Gnomad ASJ

AF:

0.700

Gnomad EAS

AF:

0.838

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.845

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.755

Gnomad OTH

AF:

0.777

GnomAD2 exomes

AF:

0.782

AC:

196687

AN:

251392

AF XY:

0.768

show subpopulations

Gnomad AFR exome

AF:

0.935

Gnomad AMR exome

AF:

0.869

Gnomad ASJ exome

AF:

0.713

Gnomad EAS exome

AF:

0.840

Gnomad FIN exome

AF:

0.850

Gnomad NFE exome

AF:

0.756

Gnomad OTH exome

AF:

0.762

GnomAD4 exome

AF:

0.761

AC:

1112468

AN:

1461860

Hom.:

425589

Cov.:

AF XY:

0.756

AC XY:

549715

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.934

AC:

31272

AN:

33480

American (AMR)

AF:

0.864

AC:

38642

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.715

AC:

18694

AN:

26136

East Asian (EAS)

AF:

0.846

AC:

33601

AN:

39700

South Asian (SAS)

AF:

0.649

AC:

55986

AN:

86256

European-Finnish (FIN)

AF:

0.846

AC:

45176

AN:

53416

Middle Eastern (MID)

AF:

0.635

AC:

3664

AN:

5768

European-Non Finnish (NFE)

AF:

0.755

AC:

839759

AN:

1111988

Other (OTH)

AF:

0.756

AC:

45674

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

16060

32120

48179

64239

80299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20400

40800

61200

81600

102000

<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:

0.814

AC:

123914

AN:

152194

Hom.:

50926

Cov.:

AF XY:

0.817

AC XY:

60757

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.932

AC:

38726

AN:

41552

American (AMR)

AF:

0.819

AC:

12522

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.700

AC:

2429

AN:

3470

East Asian (EAS)

AF:

0.837

AC:

4311

AN:

5150

South Asian (SAS)

AF:

0.651

AC:

3138

AN:

4818

European-Finnish (FIN)

AF:

0.845

AC:

8951

AN:

10588

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.755

AC:

51339

AN:

68002

Other (OTH)

AF:

0.780

AC:

1650

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1172

2344

3517

4689

5861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.761

Hom.:

33126

Bravo

AF:

0.819

TwinsUK

AF:

0.743

AC:

2756

ALSPAC

AF:

0.768

AC:

2961

ESP6500AA

AF:

0.930

AC:

4096

ESP6500EA

AF:

0.749

AC:

6445

ExAC

AF:

0.779

AC:

94634

Asia WGS

AF:

0.779

AC:

2710

AN:

3478

EpiCase

AF:

0.733

EpiControl

AF:

0.734

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

- -

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, Academic Medical Center

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

- -

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. -

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. -

Autosomal recessive ataxia, Beauce type

Benign:2

Jan 13, 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 13, 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

0.066

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.10

T;.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.034

T;T;T

MetaRNN

Benign

5.5e-7

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.17

N;.;.

PhyloP100

2.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.070

N;.;N

REVEL

Benign

0.027

Sift

Benign

0.61

T;.;T

Sift4G

Benign

0.40

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.083

MPC

0.13

ClinPred

0.0041

GERP RS

3.2

Varity_R

0.067

gMVP

0.059

Mutation Taster

=100/0

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