dbSNP rs1062577: ESR1:c.*3804T>A (chr6-152102770-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000125.4(ESR1):c.*3804T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 216,682 control chromosomes in the GnomAD database, including 1,473 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.094 ( 823 hom., cov: 32)

Exomes 𝑓: 0.12 ( 650 hom. )

Consequence

ESR1
NM_000125.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.782

Publications

35 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.*3804T>A		3_prime_UTR_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.*3804T>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.0939

AC:

14267

AN:

151988

Hom.:

819

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0892

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.262

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.0776

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0695

Gnomad OTH

AF:

0.121

GnomAD4 exome

AF:

0.117

AC:

7528

AN:

64574

Hom.:

650

Cov.:

AF XY:

0.118

AC XY:

3529

AN XY:

30024

show subpopulations

African (AFR)

AF:

0.0866

AC:

253

AN:

2920

American (AMR)

AF:

0.163

AC:

313

AN:

1918

Ashkenazi Jewish (ASJ)

AF:

0.0849

AC:

342

AN:

4030

East Asian (EAS)

AF:

0.294

AC:

2821

AN:

9580

South Asian (SAS)

AF:

0.113

AC:

AN:

548

European-Finnish (FIN)

AF:

0.0714

AC:

AN:

462

Middle Eastern (MID)

AF:

0.105

AC:

AN:

400

European-Non Finnish (NFE)

AF:

0.0795

AC:

3127

AN:

39330

Other (OTH)

AF:

0.0993

AC:

535

AN:

5386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

312

624

937

1249

1561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0940

AC:

14295

AN:

152108

Hom.:

823

Cov.:

AF XY:

0.0965

AC XY:

7179

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0897

AC:

3722

AN:

41496

American (AMR)

AF:

0.148

AC:

2259

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

284

AN:

3472

East Asian (EAS)

AF:

0.261

AC:

1351

AN:

5176

South Asian (SAS)

AF:

0.157

AC:

756

AN:

4816

European-Finnish (FIN)

AF:

0.0776

AC:

823

AN:

10602

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0695

AC:

4726

AN:

67984

Other (OTH)

AF:

0.120

AC:

252

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

657

1314

1971

2628

3285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0243

Hom.:

Bravo

AF:

0.0978

Asia WGS

AF:

0.176

AC:

614

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.6

(source)

DANN

Benign

0.83

PhyloP100

0.78

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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rs1062577

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over