rs2234693

chr6-151842200-T-Cchr6-151842200-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000125.4(ESR1):c.453-397T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,008 control chromosomes in the GnomAD database, including 16,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: 𝑓 0.47 (16806 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.453-397T>C		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.453-397T>C		intron_variant		1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70661 AN: 151890 Hom.: 16789 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.443

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

GnomAD4 genome AF: 0.465 AC: 70725 AN: 152008 Hom.: 16806 Cov.: 32 AF XY: 0.458 AC XY: 34033 AN XY: 74302

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.365

Gnomad4 ASJ AF: 0.457

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.445

Alfa AF: 0.449 Hom.: 6385

Bravo AF: 0.462

Asia WGS AF: 0.422 AC: 1465 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Myocardial infarction, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 05, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.3
DANN	Benign	0.68

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

Other links and lift over

dbSNP: rs2234693; hg19: chr6-152163335;