rs143070183

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_182961.4(SYNE1):c.11187G>T(p.Lys3729Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,614,160 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 67 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.377

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 -15 ACMG points.

PP2

Missense variant where missense usually causes diseases, SYNE1

BP4

Computational evidence support a benign effect (MetaRNN=0.006750375).

BP6

Variant 6-152353329-C-A is Benign according to our data. Variant chr6-152353329-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 198378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152353329-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 615 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.11187G>T	p.Lys3729Asn	missense_variant	69/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.11187G>T	p.Lys3729Asn	missense_variant	69/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.11142G>T	p.Lys3714Asn	missense_variant	69/146	1
SYNE1	ENST00000471834.1 linkuse as main transcript	n.4325G>T		non_coding_transcript_exon_variant	12/19	1

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

615

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00701

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00444

AC:

1116

AN:

251462

Hom.:

AF XY:

0.00447

AC XY:

607

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00775

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00773

AC:

11307

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00758

AC XY:

5512

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00174

Gnomad4 FIN exome

AF:

0.00178

Gnomad4 NFE exome

AF:

0.00950

Gnomad4 OTH exome

AF:

0.00527

GnomAD4 genome

AF:

0.00403

AC:

613

AN:

152278

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

280

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00701

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00725

Hom.:

Bravo

AF:

0.00402

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00733

AC:

ExAC

AF:

0.00437

AC:

531

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00785

EpiControl

AF:

0.00717

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2018	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. -

SYNE1-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

SYNE1: BP4, BS2 -

Autosomal recessive ataxia, Beauce type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 19, 2021

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.15

T;.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

MutationTaster

Benign

0.98

N;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.043

Sift

Benign

0.096

T;.;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.030

B;.;.

Vest4

0.33

MutPred

0.37

Loss of methylation at K3729 (P = 0.0217);.;.;

MVP

0.39

MPC

0.32

ClinPred

0.015

GERP RS

3.0

Varity_R

0.087

gMVP

0.094

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