rs2813544

Variant names:

• chr6-152104447-A-G
• rs2813544
• ENST00000427531.6:c.851-20819A>G

Variant summary

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

The ENST00000427531.6(ESR1):​c.851-20819A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,128 control chromosomes in the GnomAD database, including 3,541 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 0.21 (3541 hom., cov: 31)
• Consequence: ESR1 ENST00000427531.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• Publications: 21 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

ENSG00000298278 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001328100.2	c.851-20819A>G		intron_variant	Intron 6 of 6		NP_001315029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000427531.6	c.851-20819A>G		intron_variant	Intron 6 of 6	1		ENSP00000394721.2
ESR1	ENST00000641399.1	n.1070+5527A>G		intron_variant	Intron 6 of 6
ENSG00000298278	ENST00000754431.1	n.321-125T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32440 AN: 152010 Hom.: 3545 Cov.: 31

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.213 AC: 32440 AN: 152128 Hom.: 3541 Cov.: 31 AF XY: 0.212 AC XY: 15799 AN XY: 74376

African (AFR) AF: 0.224 AC: 9311 AN: 41508

American (AMR) AF: 0.194 AC: 2972 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 633 AN: 3468

East Asian (EAS) AF: 0.126 AC: 652 AN: 5172

South Asian (SAS) AF: 0.106 AC: 512 AN: 4822

European-Finnish (FIN) AF: 0.302 AC: 3195 AN: 10562

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14503 AN: 67980

Other (OTH) AF: 0.207 AC: 439 AN: 2116

Alfa AF: 0.211 Hom.: 6311

Bravo AF: 0.210

Asia WGS AF: 0.144 AC: 502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.42
PhyloP100		0.039
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2813544; hg19: chr6-152425582;