Genetic Variant ESR1:c.452+2600T>G (chr6-151810964-T-G) – 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.452+2600T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,206 control chromosomes in the GnomAD database, including 2,433 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 0.15 ( 2433 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

ESR1
NM_000125.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.165

Publications

7 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:

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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=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ESR1	NM_000125.4	MANE Select	c.452+2600T>G	intron	N/A	NP_000116.2
ESR1	NM_001291230.2		c.452+2600T>G	intron	N/A	NP_001278159.1
ESR1	NM_001122740.2		c.452+2600T>G	intron	N/A	NP_001116212.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ESR1	ENST00000206249.8	TSL:1 MANE Select	c.452+2600T>G	intron	N/A	ENSP00000206249.3
ESR1	ENST00000406599.5	TSL:1	c.452+2600T>G	intron	N/A	ENSP00000384064.1
ESR1	ENST00000427531.6	TSL:1	c.-68+1693T>G	intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23097

AN:

152088

Hom.:

2425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.291

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.0639

Gnomad ASJ

AF:

0.0887

Gnomad EAS

AF:

0.00615

Gnomad SAS

AF:

0.0426

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.116

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.152

AC:

23146

AN:

152206

Hom.:

2433

Cov.:

AF XY:

0.149

AC XY:

11112

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.291

AC:

12087

AN:

41498

American (AMR)

AF:

0.0638

AC:

976

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0887

AC:

308

AN:

3472

East Asian (EAS)

AF:

0.00617

AC:

AN:

5188

South Asian (SAS)

AF:

0.0429

AC:

207

AN:

4830

European-Finnish (FIN)

AF:

0.153

AC:

1623

AN:

10600

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.111

AC:

7533

AN:

68000

Other (OTH)

AF:

0.116

AC:

246

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

953

1906

2860

3813

4766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.0755

Hom.:

105

Bravo

AF:

0.152

Asia WGS

AF:

0.0420

AC:

147

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

9.6

(source)

DANN

Benign

0.79

PhyloP100

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over