6-152330578-C-T

Variant summary

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

The NM_182961.4(SYNE1):c.14107G>A(p.Asp4703Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,830 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. D4703F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0060 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 9 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0280

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=0.0069048107).

BP6

Variant 6-152330578-C-T is Benign according to our data. Variant chr6-152330578-C-T is described in ClinVar as [Benign]. Clinvar id is 130406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152330578-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00598 (911/152272) while in subpopulation AFR AF= 0.0212 (881/41536). AF 95% confidence interval is 0.02. There are 12 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 908 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.14107G>A	p.Asp4703Asn	missense_variant	78/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.14107G>A	p.Asp4703Asn	missense_variant	78/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.13894G>A	p.Asp4632Asn	missense_variant	77/146	1
SYNE1	ENST00000490135.6 linkuse as main transcript	n.1453G>A		non_coding_transcript_exon_variant	2/11	1

Frequencies

GnomAD3 genomes

AF:

0.00597

AC:

908

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00146

AC:

364

AN:

249808

Hom.:

AF XY:

0.00112

AC XY:

152

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.0211

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000625

AC:

914

AN:

1461558

Hom.:

Cov.:

AF XY:

0.000514

AC XY:

374

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0220

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00598

AC:

911

AN:

152272

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

437

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0212

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000690

Hom.:

Bravo

AF:

0.00705

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00167

AC:

203

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 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. -
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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 13, 2018

- -

Autosomal recessive ataxia, Beauce type

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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

Cadd

Benign

0.92

Dann

Benign

0.28

DEOGEN2

Benign

0.13

T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.65

T;T;T

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.45

N;.;N

REVEL

Benign

0.015

Sift

Benign

0.73

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.091

MVP

0.14

MPC

0.13

ClinPred

0.00051

GERP RS

-2.7

Varity_R

0.030

gMVP

0.064

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