rs113962905

Positions:

chr6-152294013-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_182961.4(SYNE1):c.17797G>A(p.Ala5933Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,614,080 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 12 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.11

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 -8 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=0.00496006).

BP6

Variant 6-152294013-C-T is Benign according to our data. Variant chr6-152294013-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199226.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}. Variant chr6-152294013-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.17797G>A	p.Ala5933Thr	missense_variant	94/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.17797G>A	p.Ala5933Thr	missense_variant	94/146	1	NM_182961.4	P1	Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.000782

AC:

119

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00125

AC:

315

AN:

251452

Hom.:

AF XY:

0.00127

AC XY:

173

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000906

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.000848

AC:

1239

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000931

AC XY:

677

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000488

Gnomad4 OTH exome

AF:

0.00233

GnomAD4 genome

AF:

0.000788

AC:

120

AN:

152240

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.000990

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000988

AC:

120

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 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. -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SYNE1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive ataxia, Beauce type

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance 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

Jan 23, 2024

- -

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

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

T;.;T;T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.86

D;D;D;D;D

M_CAP

Benign

0.0074

MetaRNN

Benign

0.0050

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.42

N;.;.;.;.

MutationTaster

Benign

0.79

D;D;D;D;D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;.;N;N;N

REVEL

Benign

0.018

Sift

Benign

0.20

T;.;T;T;T

Sift4G

Benign

0.15

T;T;T;.;.

Polyphen

0.010

B;.;.;.;.

Vest4

0.12

MVP

0.20

MPC

0.13

ClinPred

0.0071

GERP RS

2.6

Varity_R

0.060

gMVP

0.21

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