rs3020353

Variant names:

• chr6-152039585-C-A
• rs3020353
• NM_000125.4:c.1236-21406C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000125.4(ESR1):​c.1236-21406C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,900 control chromosomes in the GnomAD database, including 16,621 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 0.44 (16621 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.885
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1236-21406C>A		intron_variant	Intron 5 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1236-21406C>A		intron_variant	Intron 5 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66685 AN: 151780 Hom.: 16585 Cov.: 32

Gnomad AFR AF: 0.669

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.403

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

GnomAD4 genome AF: 0.440 AC: 66777 AN: 151900 Hom.: 16621 Cov.: 32 AF XY: 0.440 AC XY: 32671 AN XY: 74204

African (AFR) AF: 0.670 AC: 27736 AN: 41416

American (AMR) AF: 0.261 AC: 3978 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 955 AN: 3470

East Asian (EAS) AF: 0.599 AC: 3080 AN: 5146

South Asian (SAS) AF: 0.556 AC: 2672 AN: 4806

European-Finnish (FIN) AF: 0.401 AC: 4218 AN: 10528

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22856 AN: 67950

Other (OTH) AF: 0.404 AC: 854 AN: 2116

Alfa AF: 0.409 Hom.: 1867

Bravo AF: 0.433

Asia WGS AF: 0.580 AC: 2016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3020353; hg19: chr6-152360720;