Genetic Variant ESR1:c.452+89C>T (chr6-151808453-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000125.4(ESR1):c.452+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,144,474 control chromosomes in the GnomAD database, including 4,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.13 ( 2502 hom., cov: 32)

Exomes 𝑓: 0.023 ( 2032 hom. )

Consequence

ESR1
NM_000125.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.74

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 6-151808453-C-T is Benign according to our data. Variant chr6-151808453-C-T is described in ClinVar as [Benign]. Clinvar id is 1258285.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.452+89C>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.452+89C>T		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19532

AN:

150968

Hom.:

2487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.311

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.0686

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.128

GnomAD4 exome

AF:

0.0231

AC:

22985

AN:

993400

Hom.:

2032

AF XY:

0.0244

AC XY:

11774

AN XY:

482950

show subpopulations

Gnomad4 AFR exome

AF:

0.241

Gnomad4 AMR exome

AF:

0.142

Gnomad4 ASJ exome

AF:

0.0409

Gnomad4 EAS exome

AF:

0.236

Gnomad4 SAS exome

AF:

0.108

Gnomad4 FIN exome

AF:

0.00730

Gnomad4 NFE exome

AF:

0.00714

Gnomad4 OTH exome

AF:

0.0462

GnomAD4 genome

AF:

0.130

AC:

19579

AN:

151074

Hom.:

2502

Cov.:

AF XY:

0.133

AC XY:

9802

AN XY:

73840

show subpopulations

Gnomad4 AFR

AF:

0.312

Gnomad4 AMR

AF:

0.193

Gnomad4 ASJ

AF:

0.0686

Gnomad4 EAS

AF:

0.277

Gnomad4 SAS

AF:

0.175

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.0155

Gnomad4 OTH

AF:

0.136

Alfa

AF:

0.0699

Hom.:

154

Bravo

AF:

0.154

Asia WGS

AF:

0.255

AC:

881

AN:

3460

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.9

DANN

Benign

0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over