rs368490158

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS2_Supporting

The ENST00000367255.10(SYNE1):c.14335G>T(p.Ala4779Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4779T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SYNE1
ENST00000367255.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.93

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 Likely_benign. Variant got -4 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=0.054298818).

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.14335G>T	p.Ala4779Ser	missense_variant	78/146	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.14335G>T	p.Ala4779Ser	missense_variant	78/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.14122G>T	p.Ala4708Ser	missense_variant	77/146	1		ENSP00000396024
SYNE1	ENST00000490135.6 linkuse as main transcript	n.1681G>T		non_coding_transcript_exon_variant	2/11	1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251432

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000870

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:

0.0000109

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2023	Variant summary: SYNE1 c.14122G>T (p.Ala4708Ser) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251432 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. To our knowledge, no occurrence of c.14122G>T in individuals affected with Emery-Dreifuss Muscular Dystrophy or other SYNE1-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2015	- -

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

Mar 20, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 212337). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs368490158, gnomAD 0.09%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4708 of the SYNE1 protein (p.Ala4708Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.081

T;.;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.0077

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

L;.;.

MutationTaster

Benign

0.95

D;D;D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.060

N;.;N

REVEL

Benign

0.071

Sift

Benign

0.54

T;.;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.027

B;.;.

Vest4

0.15

MutPred

0.18

Gain of phosphorylation at A4779 (P = 0.0502);.;.;

MVP

0.31

MPC

0.12

ClinPred

0.041

GERP RS

5.0

Varity_R

0.12

gMVP

0.056

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