rs141716975

Positions:

Variant summary

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

The NM_182961.4(SYNE1):c.24952C>T(p.Leu8318Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00575 in 1,614,084 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 33 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 5.92

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 -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=0.0070774257).

BP6

Variant 6-152148069-G-A is Benign according to our data. Variant chr6-152148069-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194303.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=4}. Variant chr6-152148069-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 652 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.24952C>T	p.Leu8318Phe	missense_variant	137/146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2 linkuse as main transcript	c.1417C>T	p.Leu473Phe	missense_variant	8/18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.24952C>T	p.Leu8318Phe	missense_variant	137/146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1
SYNE1	ENST00000354674.5 linkuse as main transcript	c.1417C>T	p.Leu473Phe	missense_variant	8/18	5	NM_001347702.2	ENSP00000346701.4		F8WAI0

Frequencies

GnomAD3 genomes

AF:

0.00428

AC:

651

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00669

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00508

AC:

1269

AN:

249678

Hom.:

AF XY:

0.00527

AC XY:

712

AN XY:

135050

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00657

Gnomad FIN exome

AF:

0.00481

Gnomad NFE exome

AF:

0.00693

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00590

AC:

8623

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00592

AC XY:

4306

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.00746

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.00589

Gnomad4 FIN exome

AF:

0.00519

Gnomad4 NFE exome

AF:

0.00643

Gnomad4 OTH exome

AF:

0.00575

GnomAD4 genome

AF:

0.00428

AC:

652

AN:

152288

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

309

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.00669

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00557

Hom.:

Bravo

AF:

0.00377

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00530

AC:

643

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00581

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SYNE1: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive ataxia, Beauce type

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.24739C>T (p.L8247F) alteration is located in exon 136 (coding exon 135) of the SYNE1 gene. This alteration results from a C to T substitution at nucleotide position 24739, causing the leucine (L) at amino acid position 8247 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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 28, 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

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.;.;T;T;T;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;T;T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.0071

T;T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.8

M;.;.;.;.;.;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.6

D;.;D;D;N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0090

D;.;D;D;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T;T

Polyphen

0.91

P;.;.;.;.;.;.

Vest4

0.48

MVP

0.55

MPC

0.32

ClinPred

0.046

GERP RS

3.5

Varity_R

0.15

gMVP

0.29

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