rs4645434

Positions:

Variant summary

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

The NM_182961.4(SYNE1):c.12180G>T(p.Glu4060Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,613,888 control chromosomes in the GnomAD database, including 292,794 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 0.56 ( 24306 hom., cov: 32)

Exomes 𝑓: 0.60 ( 268488 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.394

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 in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=1.2501399E-5).

BP6

Variant 6-152344126-C-A is Benign according to our data. Variant chr6-152344126-C-A is described in ClinVar as [Benign]. Clinvar id is 130397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152344126-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.12180G>T	p.Glu4060Asp	missense_variant	74/146	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.12180G>T	p.Glu4060Asp	missense_variant	74/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.11967G>T	p.Glu3989Asp	missense_variant	73/146	1		ENSP00000396024
SYNE1	ENST00000471834.1 linkuse as main transcript	n.5318G>T		non_coding_transcript_exon_variant	17/19	1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

85068

AN:

151952

Hom.:

24292

Cov.:

show subpopulations

Gnomad AFR

AF:

0.449

Gnomad AMI

AF:

0.569

Gnomad AMR

AF:

0.604

Gnomad ASJ

AF:

0.650

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.528

Gnomad FIN

AF:

0.534

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.580

GnomAD3 exomes

AF:

0.583

AC:

146655

AN:

251458

Hom.:

43315

AF XY:

0.582

AC XY:

79063

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.600

Gnomad ASJ exome

AF:

0.653

Gnomad EAS exome

AF:

0.639

Gnomad SAS exome

AF:

0.514

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.608

Gnomad OTH exome

AF:

0.589

GnomAD4 exome

AF:

0.604

AC:

883635

AN:

1461816

Hom.:

268488

Cov.:

AF XY:

0.602

AC XY:

437602

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.439

Gnomad4 AMR exome

AF:

0.601

Gnomad4 ASJ exome

AF:

0.657

Gnomad4 EAS exome

AF:

0.645

Gnomad4 SAS exome

AF:

0.514

Gnomad4 FIN exome

AF:

0.546

Gnomad4 NFE exome

AF:

0.618

Gnomad4 OTH exome

AF:

0.597

GnomAD4 genome

AF:

0.560

AC:

85124

AN:

152072

Hom.:

24306

Cov.:

AF XY:

0.556

AC XY:

41303

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.449

Gnomad4 AMR

AF:

0.605

Gnomad4 ASJ

AF:

0.650

Gnomad4 EAS

AF:

0.640

Gnomad4 SAS

AF:

0.527

Gnomad4 FIN

AF:

0.534

Gnomad4 NFE

AF:

0.612

Gnomad4 OTH

AF:

0.582

Alfa

AF:

0.602

Hom.:

70442

Bravo

AF:

0.562

TwinsUK

AF:

0.608

AC:

2255

ALSPAC

AF:

0.629

AC:

2423

ESP6500AA

AF:

0.469

AC:

2065

ESP6500EA

AF:

0.618

AC:

5313

ExAC

AF:

0.576

AC:

69938

Asia WGS

AF:

0.593

AC:

2064

AN:

3478

EpiCase

AF:

0.602

EpiControl

AF:

0.597

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive ataxia, Beauce type

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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

Nov 02, 2018

- -

Arthrogryposis multiplex congenita 3, myogenic type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.9

DANN

Benign

0.15

DEOGEN2

Benign

0.11

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.48

T;T;T

MetaRNN

Benign

0.000013

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

N;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

N;.;N

REVEL

Benign

0.058

Sift

Benign

0.071

T;.;T

Sift4G

Uncertain

0.042

D;T;D

Polyphen

0.20

B;.;.

Vest4

0.13

MutPred

0.089

Loss of helix (P = 0.028);.;.;

MPC

0.13

ClinPred

0.0067

GERP RS

-1.3

Varity_R

0.054

gMVP

0.088

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