rs146965313

Positions:

chr6-152430535-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_182961.4(SYNE1):c.4636A>G(p.Thr1546Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.08

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 -7 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=0.02726081).

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.4636A>G	p.Thr1546Ala	missense_variant	35/146	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.4636A>G	p.Thr1546Ala	missense_variant	35/146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251346

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000145

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000482

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000388

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 05, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.4657A>G (p.T1553A) alteration is located in exon 35 (coding exon 34) of the SYNE1 gene. This alteration results from a A to G substitution at nucleotide position 4657, causing the threonine (T) at amino acid position 1553 to be replaced by an alanine (A). 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 289073). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs146965313, gnomAD 0.08%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1553 of the SYNE1 protein (p.Thr1553Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.15

T;.;T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.66

T;T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.1

M;.;.;M

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.94

N;.;N;N

REVEL

Benign

0.031

Sift

Benign

0.33

T;.;T;T

Sift4G

Benign

0.73

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.13

MVP

0.60

MPC

0.13

ClinPred

0.035

GERP RS

4.5

Varity_R

0.089

gMVP

0.065

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