rs35085679

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_182961.4(SYNE1):c.14917C>T(p.Leu4973=) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 130407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152329768-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 5236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.14917C>T	p.Leu4973=	synonymous_variant	78/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.14917C>T	p.Leu4973=	synonymous_variant	78/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.14704C>T	p.Leu4902=	synonymous_variant	77/146	1		ENSP00000396024
SYNE1	ENST00000490135.6 linkuse as main transcript	n.2263C>T		non_coding_transcript_exon_variant	2/11	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

GnomAD3 exomes

AF:

0.0332

AC:

8345

AN:

251462

Hom.:

193

AF XY:

0.0348

AC XY:

4731

AN XY:

135906

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 SAS exome

AF:

0.0467

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

Gnomad4 AFR exome

AF:

0.0305

Gnomad4 AMR exome

AF:

0.0163

Gnomad4 ASJ exome

AF:

0.0413

Gnomad4 EAS exome

AF:

0.0221

Gnomad4 SAS exome

AF:

0.0439

Gnomad4 FIN exome

AF:

0.0152

Gnomad4 NFE exome

AF:

0.0445

Gnomad4 OTH exome

AF:

0.0410

GnomAD4 genome

AF:

0.0344

AC:

5236

AN:

152292

Hom.:

101

Cov.:

AF XY:

0.0333

AC XY:

2480

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0306

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.0406

Gnomad4 EAS

AF:

0.0203

Gnomad4 SAS

AF:

0.0481

Gnomad4 FIN

AF:

0.0146

Gnomad4 NFE

AF:

0.0421

Gnomad4 OTH

AF:

0.0327

Alfa

AF:

0.0381

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 14, 2018

- -

Autosomal recessive ataxia, Beauce type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.2

DANN

Benign

0.87

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over