rs35085679

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_182961.4(SYNE1):c.14917C>T(p.Leu4973Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0407 in 1,614,170 control chromosomes in the GnomAD database, including 1,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 101 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1379 hom. )

Consequence

SYNE1
NM_182961.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.87

Publications

6 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 6-152329768-G-A is Benign according to our data. Variant chr6-152329768-G-A is described in ClinVar as Benign. ClinVar VariationId is 130407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0344 (5236/152292) while in subpopulation SAS AF = 0.0481 (232/4824). AF 95% confidence interval is 0.043. There are 101 homozygotes in GnomAd4. There are 2480 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 101 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.14917C>T	p.Leu4973Leu	synonymous_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.14917C>T	p.Leu4973Leu	synonymous_variant	Exon 78 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.14704C>T	p.Leu4902Leu	synonymous_variant	Exon 77 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000490135.6 link	n.2263C>T		non_coding_transcript_exon_variant	Exon 2 of 11	1

Frequencies

GnomAD3 genomes

AF:

0.0343

AC:

5222

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0304

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0406

Gnomad EAS

AF:

0.0204

Gnomad SAS

AF:

0.0478

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0421

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0332

AC:

8345

AN:

251462

AF XY:

0.0348

show subpopulations

Gnomad AFR exome

AF:

0.0298

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.0424

Gnomad EAS exome

AF:

0.0230

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0292

GnomAD4 exome

AF:

0.0413

AC:

60397

AN:

1461878

Hom.:

1379

Cov.:

AF XY:

0.0409

AC XY:

29737

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0305

AC:

1020

AN:

33480

American (AMR)

AF:

0.0163

AC:

730

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0413

AC:

1080

AN:

26136

East Asian (EAS)

AF:

0.0221

AC:

876

AN:

39700

South Asian (SAS)

AF:

0.0439

AC:

3783

AN:

86258

European-Finnish (FIN)

AF:

0.0152

AC:

810

AN:

53420

Middle Eastern (MID)

AF:

0.0212

AC:

122

AN:

5768

European-Non Finnish (NFE)

AF:

0.0445

AC:

49501

AN:

1111996

Other (OTH)

AF:

0.0410

AC:

2475

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

3540

7080

10621

14161

17701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1904

3808

5712

7616

9520

<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:

0.0344

AC:

5236

AN:

152292

Hom.:

101

Cov.:

AF XY:

0.0333

AC XY:

2480

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0306

AC:

1274

AN:

41572

American (AMR)

AF:

0.0195

AC:

299

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

141

AN:

3472

East Asian (EAS)

AF:

0.0203

AC:

105

AN:

5184

South Asian (SAS)

AF:

0.0481

AC:

232

AN:

4824

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0421

AC:

2865

AN:

68022

Other (OTH)

AF:

0.0327

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

257

514

772

1029

1286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0379

Hom.:

Bravo

AF:

0.0341

Asia WGS

AF:

0.0450

AC:

155

AN:

3478

EpiCase

AF:

0.0403

EpiControl

AF:

0.0408

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 29, 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, 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

- -

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. -

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

Dec 14, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:1

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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Jan 12, 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

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.2

(source)

DANN

Benign

0.87

PhyloP100

5.9

Mutation Taster

=94/6

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