dbSNP rs9479134: ESR1:c.644-12795G>A (chr6-151867860-G-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.644-12795G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 152,232 control chromosomes in the GnomAD database, including 308 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 0.048 ( 308 hom., cov: 32)

Consequence

ESR1
NM_000125.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.849

Publications

6 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=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.644-12795G>A		intron_variant	Intron 2 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.644-12795G>A		intron_variant	Intron 2 of 7	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.0482

AC:

7328

AN:

152114

Hom.:

306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0809

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0589

Gnomad ASJ

AF:

0.0450

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0145

Gnomad OTH

AF:

0.0507

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

GnomAD4 genome

AF:

0.0482

AC:

7344

AN:

152232

Hom.:

308

Cov.:

AF XY:

0.0515

AC XY:

3832

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0813

AC:

3378

AN:

41544

American (AMR)

AF:

0.0587

AC:

898

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0450

AC:

156

AN:

3468

East Asian (EAS)

AF:

0.184

AC:

951

AN:

5168

South Asian (SAS)

AF:

0.123

AC:

591

AN:

4818

European-Finnish (FIN)

AF:

0.0239

AC:

254

AN:

10610

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0145

AC:

985

AN:

68014

Other (OTH)

AF:

0.0539

AC:

114

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

346

692

1038

1384

1730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0445

Hom.:

134

Bravo

AF:

0.0507

Asia WGS

AF:

0.170

AC:

593

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.042

(source)

DANN

Benign

0.54

PhyloP100

-0.85

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