dbSNP rs6902771: ESR1:c.453-5851C>T (chr6-151836746-C-T) – 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.453-5851C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 151,940 control chromosomes in the GnomAD database, including 15,624 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 0.45 ( 15624 hom., cov: 32)

Consequence

ESR1
NM_000125.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.119

Publications

49 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=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.453-5851C>T		intron_variant	Intron 1 of 7	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.453-5851C>T		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.451

AC:

68436

AN:

151822

Hom.:

15617

Cov.:

show subpopulations

Gnomad AFR

AF:

0.477

Gnomad AMI

AF:

0.463

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.403

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.468

Gnomad OTH

AF:

0.434

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.451

AC:

68483

AN:

151940

Hom.:

15624

Cov.:

AF XY:

0.445

AC XY:

33012

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.478

AC:

19788

AN:

41426

American (AMR)

AF:

0.366

AC:

5600

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

1585

AN:

3470

East Asian (EAS)

AF:

0.402

AC:

2073

AN:

5152

South Asian (SAS)

AF:

0.409

AC:

1971

AN:

4816

European-Finnish (FIN)

AF:

0.399

AC:

4201

AN:

10540

Middle Eastern (MID)

AF:

0.452

AC:

132

AN:

292

European-Non Finnish (NFE)

AF:

0.468

AC:

31789

AN:

67940

Other (OTH)

AF:

0.437

AC:

922

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1929

3857

5786

7714

9643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.458

Hom.:

56303

Bravo

AF:

0.444

Asia WGS

AF:

0.409

AC:

1420

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.82

(source)

DANN

Benign

0.30

PhyloP100

-0.12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over