rs117501809

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_182961.4(SYNE1):c.12442G>C(p.Asp4148His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,614,180 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D4148D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 45 hom., cov: 32)

Exomes 𝑓: 0.031 ( 868 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.90

Publications

13 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=0.0064047575).

BP6

Variant 6-152336927-C-G is Benign according to our data. Variant chr6-152336927-C-G is described in ClinVar as Benign. ClinVar VariationId is 130401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0219 (3339/152338) while in subpopulation NFE AF = 0.0344 (2343/68036). AF 95% confidence interval is 0.0333. There are 45 homozygotes in GnomAd4. There are 1570 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 45 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.12442G>C	p.Asp4148His	missense_variant	Exon 76 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 link	c.12442G>C	p.Asp4148His	missense_variant	Exon 76 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.12229G>C	p.Asp4077His	missense_variant	Exon 75 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000471834.1 link	n.5580G>C		non_coding_transcript_exon_variant	Exon 19 of 19	1

Frequencies

GnomAD3 genomes

AF:

0.0219

AC:

3339

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00511

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0253

AC:

6362

AN:

251382

AF XY:

0.0267

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.00966

Gnomad ASJ exome

AF:

0.00893

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0315

AC:

46007

AN:

1461842

Hom.:

868

Cov.:

AF XY:

0.0315

AC XY:

22885

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00493

AC:

165

AN:

33480

American (AMR)

AF:

0.0101

AC:

450

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00899

AC:

235

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0319

AC:

2753

AN:

86258

European-Finnish (FIN)

AF:

0.0308

AC:

1644

AN:

53378

Middle Eastern (MID)

AF:

0.0316

AC:

182

AN:

5768

European-Non Finnish (NFE)

AF:

0.0350

AC:

38928

AN:

1112004

Other (OTH)

AF:

0.0273

AC:

1648

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

2912

5824

8737

11649

14561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1446

2892

4338

5784

7230

<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:

0.0219

AC:

3339

AN:

152338

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

1570

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00510

AC:

212

AN:

41588

American (AMR)

AF:

0.0116

AC:

178

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0280

AC:

135

AN:

4830

European-Finnish (FIN)

AF:

0.0322

AC:

342

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0344

AC:

2343

AN:

68036

Other (OTH)

AF:

0.0161

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

172

344

517

689

861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0287

Hom.:

Bravo

AF:

0.0192

TwinsUK

AF:

0.0345

AC:

128

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0326

AC:

280

ExAC

AF:

0.0272

AC:

3298

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0343

EpiControl

AF:

0.0319

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

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. -

Mar 11, 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. -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 07, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:1

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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

D;.;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

D;.;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.68

MPC

0.66

ClinPred

0.011

GERP RS

5.5

Varity_R

0.58

gMVP

0.46

Mutation Taster

=92/8

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