rs2295190

Positions:

chr6-152122609-G-T

Variant summary

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

The NM_182961.4(SYNE1):c.26221C>A(p.Leu8741Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,614,114 control chromosomes in the GnomAD database, including 15,499 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 0.10 ( 1082 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14417 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.64

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:

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ESR1 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=0.0018197596).

BP6

Variant 6-152122609-G-T is Benign according to our data. Variant chr6-152122609-G-T is described in ClinVar as [Benign]. Clinvar id is 130436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152122609-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 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.26221C>A	p.Leu8741Met	missense_variant	146/146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2 linkuse as main transcript	c.2755C>A	p.Leu919Met	missense_variant	18/18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.26221C>A	p.Leu8741Met	missense_variant	146/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1
SYNE1	ENST00000354674.5 linkuse as main transcript	c.2755C>A	p.Leu919Met	missense_variant	18/18	5	NM_001347702.2	ENSP00000346701

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15685

AN:

152156

Hom.:

1081

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0318

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.0549

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.0616

Gnomad SAS

AF:

0.0932

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.147

Gnomad OTH

AF:

0.0774

GnomAD3 exomes

AF:

0.115

AC:

28800

AN:

251356

Hom.:

2125

AF XY:

0.118

AC XY:

16002

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0276

Gnomad AMR exome

AF:

0.0432

Gnomad ASJ exome

AF:

0.117

Gnomad EAS exome

AF:

0.0552

Gnomad SAS exome

AF:

0.0895

Gnomad FIN exome

AF:

0.196

Gnomad NFE exome

AF:

0.150

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.136

AC:

198384

AN:

1461840

Hom.:

14417

Cov.:

AF XY:

0.135

AC XY:

97926

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0262

Gnomad4 AMR exome

AF:

0.0435

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.0825

Gnomad4 SAS exome

AF:

0.0923

Gnomad4 FIN exome

AF:

0.196

Gnomad4 NFE exome

AF:

0.147

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.103

AC:

15692

AN:

152274

Hom.:

1082

Cov.:

AF XY:

0.102

AC XY:

7604

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0318

Gnomad4 AMR

AF:

0.0548

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.0617

Gnomad4 SAS

AF:

0.0931

Gnomad4 FIN

AF:

0.195

Gnomad4 NFE

AF:

0.147

Gnomad4 OTH

AF:

0.0799

Alfa

AF:

0.131

Hom.:

2471

Bravo

AF:

0.0875

TwinsUK

AF:

0.144

AC:

533

ALSPAC

AF:

0.156

AC:

600

ESP6500AA

AF:

0.0345

AC:

152

ESP6500EA

AF:

0.140

AC:

1202

ExAC

AF:

0.118

AC:

14339

Asia WGS

AF:

0.0960

AC:

337

AN:

3478

EpiCase

AF:

0.133

EpiControl

AF:

0.129

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 02, 2018

- -

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

0.15

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.;.;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

T;T;D;T;D

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

M;.;.;.;.

MutationTaster

Benign

3.4e-18

P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

N;.;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.030

D;.;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D

Polyphen

0.99

D;.;.;.;.

Vest4

0.25

MPC

0.51

ClinPred

0.012

GERP RS

0.63

Varity_R

0.30

gMVP

0.32

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