rs2228480

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000125.4(ESR1):c.1782G>A(p.Thr594Thr) 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

Publications

182 publications found

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 Gene-Disease associations (from GenCC):

estrogen resistance syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ESR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.1782G>A	p.Thr594Thr	synonymous_variant	Exon 8 of 8	ENST00000206249.8	NP_000116.2	P03372-1G4XH65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 link	c.1782G>A	p.Thr594Thr	synonymous_variant	Exon 8 of 8	1	NM_000125.4	ENSP00000206249.3		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

GnomAD2 exomes

AF:

0.194

AC:

48493

AN:

250380

AF XY:

0.190

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 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

African (AFR)

AF:

0.150

AC:

5015

AN:

33448

American (AMR)

AF:

0.265

AC:

11831

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

3666

AN:

26128

East Asian (EAS)

AF:

0.192

AC:

7631

AN:

39684

South Asian (SAS)

AF:

0.191

AC:

16429

AN:

86220

European-Finnish (FIN)

AF:

0.186

AC:

9911

AN:

53360

Middle Eastern (MID)

AF:

0.111

AC:

641

AN:

5764

European-Non Finnish (NFE)

AF:

0.190

AC:

210969

AN:

1110376

Other (OTH)

AF:

0.179

AC:

10809

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

11608

23216

34825

46433

58041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7550

15100

22650

30200

37750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.179

AC:

27235

AN:

152128

Hom.:

2469

Cov.:

AF XY:

0.181

AC XY:

13439

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.154

AC:

6380

AN:

41524

American (AMR)

AF:

0.231

AC:

3523

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

455

AN:

3468

East Asian (EAS)

AF:

0.206

AC:

1061

AN:

5158

South Asian (SAS)

AF:

0.190

AC:

915

AN:

4822

European-Finnish (FIN)

AF:

0.183

AC:

1935

AN:

10590

Middle Eastern (MID)

AF:

0.0856

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.184

AC:

12499

AN:

67982

Other (OTH)

AF:

0.162

AC:

342

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1177

2354

3532

4709

5886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.180

Hom.:

10220

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

ESR1-related disorder

Benign:1

Mar 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

not provided

Benign:1

Aug 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

Benign:1

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Migraine with or without aura, susceptibility to

Other:1

Jun 01, 2004

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.093

(source)

DANN

Benign

0.50

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over