rs3020343

Variant names:

• chr6-151733228-C-T
• rs3020343
• ENST00000404742.5:c.-71+31223C>T

Variant summary

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

The ENST00000404742.5(ESR1):​c.-71+31223C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 152,026 control chromosomes in the GnomAD database, including 19,158 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 0.48 (19158 hom., cov: 32)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.912
• Publications: 15 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001122742.2	c.-71+31223C>T		intron_variant	Intron 2 of 9		NP_001116214.1
ESR1	NM_001385568.1	c.-71+31223C>T		intron_variant	Intron 2 of 9		NP_001372497.1
ESR1	NM_001385570.1	c.-71+31223C>T		intron_variant	Intron 2 of 8		NP_001372499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000404742.5	c.-71+31223C>T		intron_variant	Intron 2 of 2	1		ENSP00000385373.1
ESR1	ENST00000473497.5	n.204+31223C>T		intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5	c.-71+31223C>T		intron_variant	Intron 2 of 9	5		ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73346 AN: 151908 Hom.: 19157 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.483 AC: 73362 AN: 152026 Hom.: 19158 Cov.: 32 AF XY: 0.486 AC XY: 36109 AN XY: 74326

African (AFR) AF: 0.310 AC: 12834 AN: 41448

American (AMR) AF: 0.491 AC: 7492 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1882 AN: 3470

East Asian (EAS) AF: 0.231 AC: 1199 AN: 5180

South Asian (SAS) AF: 0.394 AC: 1894 AN: 4802

European-Finnish (FIN) AF: 0.697 AC: 7363 AN: 10570

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.574 AC: 39028 AN: 67964

Other (OTH) AF: 0.452 AC: 954 AN: 2112

Alfa AF: 0.535 Hom.: 94194

Bravo AF: 0.457

Asia WGS AF: 0.337 AC: 1175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0090
DANN	Benign	0.65
PhyloP100		-0.91
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: rs3020343; hg19: chr6-152054363; COSMIC: COSV68604260;