6-152330899-A-T

Position:

chr6-152330899-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.13786T>A(p.Ser4596Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,614,046 control chromosomes in the GnomAD database, including 473,479 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 0.80 ( 49272 hom., cov: 32)

Exomes 𝑓: 0.76 ( 424207 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.49

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=7.340609E-7).

BP6

Variant 6-152330899-A-T is Benign according to our data. Variant chr6-152330899-A-T is described in ClinVar as [Benign]. Clinvar id is 130404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152330899-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 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.13786T>A	p.Ser4596Thr	missense_variant	78/146	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.13786T>A	p.Ser4596Thr	missense_variant	78/146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.13573T>A	p.Ser4525Thr	missense_variant	77/146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000490135.6 linkuse as main transcript	n.1132T>A		non_coding_transcript_exon_variant	2/11	1

Frequencies

GnomAD3 genomes

AF:

0.802

AC:

121997

AN:

152102

Hom.:

49213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.889

Gnomad AMI

AF:

0.717

Gnomad AMR

AF:

0.815

Gnomad ASJ

AF:

0.700

Gnomad EAS

AF:

0.847

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.845

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.755

Gnomad OTH

AF:

0.766

GnomAD3 exomes

AF:

0.780

AC:

195948

AN:

251358

Hom.:

77245

AF XY:

0.766

AC XY:

104127

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.891

Gnomad AMR exome

AF:

0.867

Gnomad ASJ exome

AF:

0.712

Gnomad EAS exome

AF:

0.846

Gnomad SAS exome

AF:

0.647

Gnomad FIN exome

AF:

0.850

Gnomad NFE exome

AF:

0.756

Gnomad OTH exome

AF:

0.759

GnomAD4 exome

AF:

0.760

AC:

1110859

AN:

1461826

Hom.:

424207

Cov.:

AF XY:

0.755

AC XY:

549048

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.888

Gnomad4 AMR exome

AF:

0.861

Gnomad4 ASJ exome

AF:

0.714

Gnomad4 EAS exome

AF:

0.854

Gnomad4 SAS exome

AF:

0.650

Gnomad4 FIN exome

AF:

0.846

Gnomad4 NFE exome

AF:

0.755

Gnomad4 OTH exome

AF:

0.754

GnomAD4 genome

AF:

0.802

AC:

122114

AN:

152220

Hom.:

49272

Cov.:

AF XY:

0.805

AC XY:

59939

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.889

Gnomad4 AMR

AF:

0.815

Gnomad4 ASJ

AF:

0.700

Gnomad4 EAS

AF:

0.847

Gnomad4 SAS

AF:

0.651

Gnomad4 FIN

AF:

0.845

Gnomad4 NFE

AF:

0.755

Gnomad4 OTH

AF:

0.769

Alfa

AF:

0.760

Hom.:

32931

Bravo

AF:

0.806

TwinsUK

AF:

0.743

AC:

2756

ALSPAC

AF:

0.768

AC:

2958

ESP6500AA

AF:

0.887

AC:

3910

ESP6500EA

AF:

0.749

AC:

6441

ExAC

AF:

0.776

AC:

94209

Asia WGS

AF:

0.777

AC:

2704

AN:

3478

EpiCase

AF:

0.732

EpiControl

AF:

0.735

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -

Autosomal recessive ataxia, Beauce type

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 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: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 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. -

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

- -

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

0.060

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0010

DANN

Benign

0.20

DEOGEN2

Benign

0.085

T;.;T

Eigen

Benign

-2.8

Eigen_PC

Benign

-2.9

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.010

T;T;T

MetaRNN

Benign

7.3e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.025

N;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.22

N;.;N

REVEL

Benign

0.049

Sift

Benign

0.57

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.089

MPC

0.12

ClinPred

0.024

GERP RS

-12

Varity_R

0.039

gMVP

0.057

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