Genetic Variant ESR1:c.-70-3534T>C (chr6-151804309-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000404742.5(ESR1):c.-70-3534T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 152,098 control chromosomes in the GnomAD database, including 46,037 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 0.77 ( 46025 hom., cov: 30)

Exomes 𝑓: 0.81 ( 12 hom. )

Consequence

ESR1
ENST00000404742.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.69

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=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
ESR1	NM_001122742.2 link	c.-70-3534T>C	intron_variant	Intron 2 of 9	NP_001116214.1
ESR1	NM_001385568.1 link	c.-70-3534T>C	intron_variant	Intron 2 of 9	NP_001372497.1
ESR1	NM_001385570.1 link	c.-70-3534T>C	intron_variant	Intron 2 of 8	NP_001372499.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
ESR1	ENST00000404742.5 link	c.-70-3534T>C	intron_variant	Intron 2 of 2	1	ENSP00000385373.1
ESR1	ENST00000473497.5 link	n.205-3534T>C	intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5 link	c.-70-3534T>C	intron_variant	Intron 2 of 9	5	ENSP00000405330.1
ESR1	ENST00000338799.9 link	c.-1582T>C	upstream_gene_variant		5	ENSP00000342630.5

Frequencies

GnomAD3 genomes

AF:

0.768

AC:

116754

AN:

151944

Hom.:

45970

Cov.:

show subpopulations

Gnomad AFR

AF:

0.939

Gnomad AMI

AF:

0.619

Gnomad AMR

AF:

0.776

Gnomad ASJ

AF:

0.694

Gnomad EAS

AF:

0.938

Gnomad SAS

AF:

0.781

Gnomad FIN

AF:

0.699

Gnomad MID

AF:

0.690

Gnomad NFE

AF:

0.667

Gnomad OTH

AF:

0.748

GnomAD4 exome

AF:

0.806

AC:

AN:

Hom.:

AF XY:

0.769

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.750

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.818

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.769

AC:

116869

AN:

152062

Hom.:

46025

Cov.:

AF XY:

0.771

AC XY:

57325

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.939

AC:

38990

AN:

41520

American (AMR)

AF:

0.777

AC:

11872

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.694

AC:

2409

AN:

3470

East Asian (EAS)

AF:

0.938

AC:

4833

AN:

5154

South Asian (SAS)

AF:

0.780

AC:

3751

AN:

4810

European-Finnish (FIN)

AF:

0.699

AC:

7366

AN:

10544

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.667

AC:

45298

AN:

67960

Other (OTH)

AF:

0.749

AC:

1584

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1316

2632

3949

5265

6581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.697

Hom.:

120926

Bravo

AF:

0.779

Asia WGS

AF:

0.859

AC:

2986

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.022

(source)

DANN

Benign

0.59

PhyloP100

-2.7

PromoterAI

0.017

Neutral

(source)

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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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