rs145911138

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_182961.4(SYNE1):c.10598G>A(p.Arg3533His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,614,102 control chromosomes in the GnomAD database, including 306 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3533C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 26 hom., cov: 32)

Exomes 𝑓: 0.018 ( 280 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.97

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, SYNE1

BP4

Computational evidence support a benign effect (MetaRNN=0.0023521185).

BP6

Variant 6-152358383-C-T is Benign according to our data. Variant chr6-152358383-C-T is described in ClinVar as [Benign]. Clinvar id is 130391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152358383-C-T is described in Lovd as [Likely_benign]. Variant chr6-152358383-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1870/152268) while in subpopulation NFE AF= 0.018 (1224/68030). AF 95% confidence interval is 0.0172. There are 26 homozygotes in gnomad4. There are 881 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 1871 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.10598G>A	p.Arg3533His	missense_variant	66/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.10598G>A	p.Arg3533His	missense_variant	66/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.10619G>A	p.Arg3540His	missense_variant	66/146	1
SYNE1	ENST00000471834.1 linkuse as main transcript	n.3736G>A		non_coding_transcript_exon_variant	9/19	1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1871

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0692

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.0338

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0178

GnomAD3 exomes

AF:

0.0125

AC:

3135

AN:

251466

Hom.:

AF XY:

0.0128

AC XY:

1735

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00320

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0143

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0179

AC:

26129

AN:

1461834

Hom.:

280

Cov.:

AF XY:

0.0177

AC XY:

12840

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.00438

Gnomad4 ASJ exome

AF:

0.0267

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0148

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0198

Gnomad4 OTH exome

AF:

0.0184

GnomAD4 genome

AF:

0.0123

AC:

1870

AN:

152268

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

881

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.0338

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.0136

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.0164

Hom.:

Bravo

AF:

0.0114

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0118

AC:

1436

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0176

EpiControl

AF:

0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2019	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2023	- -

not specified

Benign:3

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autosomal recessive ataxia, Beauce type

Benign:1

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:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

Cadd

Benign

Dann

Benign

0.93

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

L;.;.

MutationTaster

Benign

0.97

D;D;D;D;D

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.028

Sift

Benign

0.16

T;.;T

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.025

B;.;.

Vest4

0.23

MPC

0.17

ClinPred

0.0092

GERP RS

3.2

Varity_R

0.083

gMVP

0.072

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