rs214976

Positions:

Variant summary

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

The NM_182961.4(SYNE1):c.3104T>C(p.Val1035Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,613,752 control chromosomes in the GnomAD database, including 167,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 22767 hom., cov: 31)

Exomes 𝑓: 0.44 ( 144873 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.64

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=5.3290587E-6).

BP6

Variant 6-152451129-A-G is Benign according to our data. Variant chr6-152451129-A-G is described in ClinVar as [Benign]. Clinvar id is 130438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152451129-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 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.3104T>C	p.Val1035Ala	missense_variant	26/146	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.3104T>C	p.Val1035Ala	missense_variant	26/146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.524

AC:

79540

AN:

151822

Hom.:

22727

Cov.:

show subpopulations

Gnomad AFR

AF:

0.746

Gnomad AMI

AF:

0.281

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.495

Gnomad EAS

AF:

0.758

Gnomad SAS

AF:

0.540

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.418

Gnomad OTH

AF:

0.530

GnomAD3 exomes

AF:

0.469

AC:

117956

AN:

251420

Hom.:

29947

AF XY:

0.470

AC XY:

63876

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.754

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.487

Gnomad EAS exome

AF:

0.764

Gnomad SAS exome

AF:

0.521

Gnomad FIN exome

AF:

0.400

Gnomad NFE exome

AF:

0.423

Gnomad OTH exome

AF:

0.446

GnomAD4 exome

AF:

0.436

AC:

637374

AN:

1461814

Hom.:

144873

Cov.:

AF XY:

0.439

AC XY:

319127

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.756

Gnomad4 AMR exome

AF:

0.339

Gnomad4 ASJ exome

AF:

0.484

Gnomad4 EAS exome

AF:

0.779

Gnomad4 SAS exome

AF:

0.522

Gnomad4 FIN exome

AF:

0.395

Gnomad4 NFE exome

AF:

0.410

Gnomad4 OTH exome

AF:

0.470

GnomAD4 genome

AF:

0.524

AC:

79634

AN:

151938

Hom.:

22767

Cov.:

AF XY:

0.522

AC XY:

38758

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.747

Gnomad4 AMR

AF:

0.423

Gnomad4 ASJ

AF:

0.495

Gnomad4 EAS

AF:

0.759

Gnomad4 SAS

AF:

0.540

Gnomad4 FIN

AF:

0.386

Gnomad4 NFE

AF:

0.418

Gnomad4 OTH

AF:

0.530

Alfa

AF:

0.448

Hom.:

39272

Bravo

AF:

0.536

TwinsUK

AF:

0.408

AC:

1512

ALSPAC

AF:

0.403

AC:

1552

ESP6500AA

AF:

0.734

AC:

3232

ESP6500EA

AF:

0.430

AC:

3694

ExAC

AF:

0.481

AC:

58402

Asia WGS

AF:

0.628

AC:

2186

AN:

3478

EpiCase

AF:

0.432

EpiControl

AF:

0.429

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive ataxia, Beauce type

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

- -

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

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;T;.;.;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D;D;D;D

MetaRNN

Benign

0.0000053

T;T;T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.9

L;.;.;L;.;L

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.4

N;.;N;D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0060

D;.;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Polyphen

0.0090

B;.;.;B;B;.

Vest4

0.38

MPC

0.23

ClinPred

0.048

GERP RS

5.8

Varity_R

0.17

gMVP

0.39

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