chr6-152326546-A-T

Position:

chr6-152326546-A-T

Variant summary

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

The NM_182961.4(SYNE1):c.15043T>A(p.Leu5015Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,614,054 control chromosomes in the GnomAD database, including 476,515 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 0.81 ( 50926 hom., cov: 33)

Exomes 𝑓: 0.76 ( 425589 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.93

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:

SYNE1 (HGNC:):

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=5.5081324E-7).

BP6

Variant 6-152326546-A-T is Benign according to our data. Variant chr6-152326546-A-T is described in ClinVar as [Benign]. Clinvar id is 130408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152326546-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.924 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.15043T>A	p.Leu5015Met	missense_variant	79/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.15043T>A	p.Leu5015Met	missense_variant	79/146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.14830T>A	p.Leu4944Met	missense_variant	78/146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000490135.6 linkuse as main transcript	n.2389T>A		non_coding_transcript_exon_variant	3/11	1

Frequencies

GnomAD3 genomes

AF:

0.814

AC:

123789

AN:

152076

Hom.:

50859

Cov.:

show subpopulations

Gnomad AFR

AF:

0.932

Gnomad AMI

AF:

0.720

Gnomad AMR

AF:

0.819

Gnomad ASJ

AF:

0.700

Gnomad EAS

AF:

0.838

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.845

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.755

Gnomad OTH

AF:

0.777

GnomAD3 exomes

AF:

0.782

AC:

196687

AN:

251392

Hom.:

77897

AF XY:

0.768

AC XY:

104400

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.935

Gnomad AMR exome

AF:

0.869

Gnomad ASJ exome

AF:

0.713

Gnomad EAS exome

AF:

0.840

Gnomad SAS exome

AF:

0.646

Gnomad FIN exome

AF:

0.850

Gnomad NFE exome

AF:

0.756

Gnomad OTH exome

AF:

0.762

GnomAD4 exome

AF:

0.761

AC:

1112468

AN:

1461860

Hom.:

425589

Cov.:

AF XY:

0.756

AC XY:

549715

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.934

Gnomad4 AMR exome

AF:

0.864

Gnomad4 ASJ exome

AF:

0.715

Gnomad4 EAS exome

AF:

0.846

Gnomad4 SAS exome

AF:

0.649

Gnomad4 FIN exome

AF:

0.846

Gnomad4 NFE exome

AF:

0.755

Gnomad4 OTH exome

AF:

0.756

GnomAD4 genome

AF:

0.814

AC:

123914

AN:

152194

Hom.:

50926

Cov.:

AF XY:

0.817

AC XY:

60757

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.932

Gnomad4 AMR

AF:

0.819

Gnomad4 ASJ

AF:

0.700

Gnomad4 EAS

AF:

0.837

Gnomad4 SAS

AF:

0.651

Gnomad4 FIN

AF:

0.845

Gnomad4 NFE

AF:

0.755

Gnomad4 OTH

AF:

0.780

Alfa

AF:

0.761

Hom.:

33126

Bravo

AF:

0.819

TwinsUK

AF:

0.743

AC:

2756

ALSPAC

AF:

0.768

AC:

2961

ESP6500AA

AF:

0.930

AC:

4096

ESP6500EA

AF:

0.749

AC:

6445

ExAC

AF:

0.779

AC:

94634

Asia WGS

AF:

0.779

AC:

2710

AN:

3478

EpiCase

AF:

0.733

EpiControl

AF:

0.734

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, 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	-	- -

Autosomal recessive ataxia, Beauce type

Benign:2

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. -
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	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

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

0.066

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.10

T;.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.034

T;T;T

MetaRNN

Benign

5.5e-7

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.17

N;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.070

N;.;N

REVEL

Benign

0.027

Sift

Benign

0.61

T;.;T

Sift4G

Benign

0.40

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.083

MPC

0.13

ClinPred

0.0041

GERP RS

3.2

Varity_R

0.067

gMVP

0.059

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