rs2228480

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000125.4(ESR1):c.1782G>A(p.Thr594=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,612,120 control chromosomes in the GnomAD database, including 29,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2469 hom., cov: 32)

Exomes 𝑓: 0.19 ( 26882 hom. )

Consequence

ESR1
NM_000125.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.344

Variant links:

Genes affected

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 6-152098960-G-A is Benign according to our data. Variant chr6-152098960-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1263746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.344 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_000125.4 linkuse as main transcript	c.1782G>A	p.Thr594=	synonymous_variant	8/8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 linkuse as main transcript	c.1782G>A	p.Thr594=	synonymous_variant	8/8	1	NM_000125.4	ENSP00000206249	P1	P03372-1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27192

AN:

152006

Hom.:

2462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.230

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.205

Gnomad SAS

AF:

0.190

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.0892

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.155

GnomAD3 exomes

AF:

0.194

AC:

48493

AN:

250380

Hom.:

4939

AF XY:

0.190

AC XY:

25680

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.271

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.219

Gnomad SAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.170

GnomAD4 exome

AF:

0.190

AC:

276902

AN:

1459992

Hom.:

26882

Cov.:

AF XY:

0.189

AC XY:

136931

AN XY:

726374

show subpopulations

Gnomad4 AFR exome

AF:

0.150

Gnomad4 AMR exome

AF:

0.265

Gnomad4 ASJ exome

AF:

0.140

Gnomad4 EAS exome

AF:

0.192

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.186

Gnomad4 NFE exome

AF:

0.190

Gnomad4 OTH exome

AF:

0.179

GnomAD4 genome

AF:

0.179

AC:

27235

AN:

152128

Hom.:

2469

Cov.:

AF XY:

0.181

AC XY:

13439

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.231

Gnomad4 ASJ

AF:

0.131

Gnomad4 EAS

AF:

0.206

Gnomad4 SAS

AF:

0.190

Gnomad4 FIN

AF:

0.183

Gnomad4 NFE

AF:

0.184

Gnomad4 OTH

AF:

0.162

Alfa

AF:

0.176

Hom.:

4394

Bravo

AF:

0.182

Asia WGS

AF:

0.212

AC:

737

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.169

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2018

This variant is associated with the following publications: (PMID: 15934440, 19636371, 19860576) -

ESR1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cancer of breast;C1832662:Myocardial infarction, susceptibility to;C3809250:Estrogen resistance syndrome;C3887485:Migraine with or without aura, susceptibility to, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

Migraine with or without aura, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.093

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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