rs150170988

Positions:

chr6-152364955-G-T

Variant summary

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

The NM_182961.4(SYNE1):c.10037C>A(p.Ser3346Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,614,202 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 38 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.03

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 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=0.0111064315).

BP6

Variant 6-152364955-G-T is Benign according to our data. Variant chr6-152364955-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 198335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152364955-G-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 588 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.10037C>A	p.Ser3346Tyr	missense_variant	63/146	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.10037C>A	p.Ser3346Tyr	missense_variant	63/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.10058C>A	p.Ser3353Tyr	missense_variant	63/146	1		ENSP00000396024
SYNE1	ENST00000471834.1 linkuse as main transcript	n.3175C>A		non_coding_transcript_exon_variant	6/19	1

Frequencies

GnomAD3 genomes

AF:

0.00386

AC:

588

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00606

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00373

AC:

939

AN:

251488

Hom.:

AF XY:

0.00389

AC XY:

529

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00219

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00606

AC:

8866

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00593

AC XY:

4310

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00231

Gnomad4 FIN exome

AF:

0.00354

Gnomad4 NFE exome

AF:

0.00726

Gnomad4 OTH exome

AF:

0.00435

GnomAD4 genome

AF:

0.00386

AC:

588

AN:

152320

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.00606

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00525

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00432

AC:

524

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00594

EpiControl

AF:

0.00605

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SYNE1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2017	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	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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. -

SYNE1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2020

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;C5193121:Arthrogryposis multiplex congenita 3, myogenic type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

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

0.076

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.34

T;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

D;T;D

M_CAP

Benign

0.0099

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.84

L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.096

Sift

Benign

0.098

T;.;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.28

MVP

0.35

MPC

0.17

ClinPred

0.021

GERP RS

0.86

Varity_R

0.065

gMVP

0.22

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