rs111250109

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_182961.4(SYNE1):c.5190T>A(p.Asp1730Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,614,108 control chromosomes in the GnomAD database, including 1,838 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 172 hom., cov: 33)

Exomes 𝑓: 0.046 ( 1666 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.22

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, SYNE1

BP4

Computational evidence support a benign effect (MetaRNN=0.0015822649).

BP6

Variant 6-152425458-A-T is Benign according to our data. Variant chr6-152425458-A-T is described in ClinVar as [Benign]. Clinvar id is 130446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152425458-A-T is described in Lovd as [Benign]. Variant chr6-152425458-A-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.5190T>A	p.Asp1730Glu	missense_variant	39/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.5190T>A	p.Asp1730Glu	missense_variant	39/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.5211T>A	p.Asp1737Glu	missense_variant	39/146	1
SYNE1	ENST00000461872.6 linkuse as main transcript	n.5408T>A		non_coding_transcript_exon_variant	37/55	1

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6798

AN:

152166

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0343

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0393

Gnomad ASJ

AF:

0.0665

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0377

Gnomad FIN

AF:

0.0446

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0551

Gnomad OTH

AF:

0.0549

GnomAD3 exomes

AF:

0.0427

AC:

10739

AN:

251304

Hom.:

319

AF XY:

0.0437

AC XY:

5940

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.0356

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0669

Gnomad EAS exome

AF:

0.00130

Gnomad SAS exome

AF:

0.0361

Gnomad FIN exome

AF:

0.0498

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0467

GnomAD4 exome

AF:

0.0459

AC:

67119

AN:

1461824

Hom.:

1666

Cov.:

AF XY:

0.0460

AC XY:

33420

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0355

Gnomad4 AMR exome

AF:

0.0259

Gnomad4 ASJ exome

AF:

0.0666

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.0360

Gnomad4 FIN exome

AF:

0.0478

Gnomad4 NFE exome

AF:

0.0489

Gnomad4 OTH exome

AF:

0.0449

GnomAD4 genome

AF:

0.0448

AC:

6815

AN:

152284

Hom.:

172

Cov.:

AF XY:

0.0440

AC XY:

3275

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0346

Gnomad4 AMR

AF:

0.0392

Gnomad4 ASJ

AF:

0.0665

Gnomad4 EAS

AF:

0.00271

Gnomad4 SAS

AF:

0.0377

Gnomad4 FIN

AF:

0.0446

Gnomad4 NFE

AF:

0.0551

Gnomad4 OTH

AF:

0.0539

Alfa

AF:

0.0541

Hom.:

Bravo

AF:

0.0424

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.0415

AC:

183

ESP6500EA

AF:

0.0516

AC:

444

ExAC

AF:

0.0442

AC:

5363

Asia WGS

AF:

0.0320

AC:

111

AN:

3478

EpiCase

AF:

0.0543

EpiControl

AF:

0.0527

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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	Jan 25, 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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.86

Cadd

Benign

0.0070

Dann

Benign

0.81

DEOGEN2

Benign

0.090

T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.63

T;T;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.24

N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.19

N;.;N

REVEL

Benign

0.041

Sift

Benign

0.74

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.048

MutPred

0.26

Gain of ubiquitination at K1733 (P = 0.1204);.;.;

MPC

0.12

ClinPred

0.00058

GERP RS

-6.3

Varity_R

0.038

gMVP

0.024

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