6-152122621-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182961.4(SYNE1):c.26209G>A(p.Gly8737Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,614,110 control chromosomes in the GnomAD database, including 518 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 (★★).

Frequency

Genomes: 𝑓 0.011 ( 69 hom., cov: 33)

Exomes 𝑓: 0.0082 ( 449 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.54

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00387156).

BP6

Variant 6-152122621-C-T is Benign according to our data. Variant chr6-152122621-C-T is described in ClinVar as [Benign]. Clinvar id is 130435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.26209G>A	p.Gly8737Ser	missense_variant	Exon 146 of 146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2 link	c.2743G>A	p.Gly915Ser	missense_variant	Exon 18 of 18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 link	c.26209G>A	p.Gly8737Ser	missense_variant	Exon 146 of 146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1
SYNE1	ENST00000354674.5 link	c.2743G>A	p.Gly915Ser	missense_variant	Exon 18 of 18	5	NM_001347702.2	ENSP00000346701.4		F8WAI0

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1651

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.0992

Gnomad SAS

AF:

0.0373

Gnomad FIN

AF:

0.0721

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.0185

AC:

4661

AN:

251344

Hom.:

172

AF XY:

0.0191

AC XY:

2589

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00337

Gnomad EAS exome

AF:

0.104

Gnomad SAS exome

AF:

0.0365

Gnomad FIN exome

AF:

0.0607

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.00816

AC:

11932

AN:

1461832

Hom.:

449

Cov.:

AF XY:

0.00895

AC XY:

6510

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.0355

Gnomad4 FIN exome

AF:

0.0578

Gnomad4 NFE exome

AF:

0.000541

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.0109

AC:

1653

AN:

152278

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1112

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.0994

Gnomad4 SAS

AF:

0.0377

Gnomad4 FIN

AF:

0.0721

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.00995

Alfa

AF:

0.00188

Hom.:

Bravo

AF:

0.00507

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0176

AC:

2139

Asia WGS

AF:

0.0650

AC:

225

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Feb 05, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.26

DANN

Benign

0.75

DEOGEN2

Benign

0.099

T;.;.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.70

T;T;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;.;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.49

N;.;N;N;N

REVEL

Benign

0.019

Sift

Benign

0.97

T;.;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.

Vest4

0.064

MPC

0.13

ClinPred

0.0023

GERP RS

-4.8

Varity_R

0.058

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