rs851982

Variant names:

• chr6-151703850-T-C
• rs851982
• ENST00000404742.5:c.-71+1845T>C

Variant summary

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

The NM_001122742.2(ESR1):​c.-71+1845T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 152,002 control chromosomes in the GnomAD database, including 8,955 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 0.33 (8955 hom., cov: 32)
• Consequence: ESR1 NM_001122742.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 40 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122742.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_001122742.2		c.-71+1845T>C		intron	N/A	NP_001116214.1	G4XH65
	ESR1	NM_001385568.1		c.-71+1845T>C		intron	N/A	NP_001372497.1	P03372-1
	ESR1	NM_001385570.1		c.-71+1845T>C		intron	N/A	NP_001372499.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000404742.5	TSL:1	c.-71+1845T>C		intron	N/A	ENSP00000385373.1	Q5T5H8
	ESR1	ENST00000473497.5	TSL:1	n.204+1845T>C		intron	N/A
	ESR1	ENST00000440973.5	TSL:5	c.-71+1845T>C		intron	N/A	ENSP00000405330.1	P03372-1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50194 AN: 151884 Hom.: 8957 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.330 AC: 50208 AN: 152002 Hom.: 8955 Cov.: 32 AF XY: 0.328 AC XY: 24396 AN XY: 74312

African (AFR) AF: 0.217 AC: 8981 AN: 41456

American (AMR) AF: 0.341 AC: 5215 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3472

East Asian (EAS) AF: 0.129 AC: 668 AN: 5160

South Asian (SAS) AF: 0.219 AC: 1055 AN: 4812

European-Finnish (FIN) AF: 0.448 AC: 4723 AN: 10544

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

European-Non Finnish (NFE) AF: 0.399 AC: 27125 AN: 67962

Other (OTH) AF: 0.307 AC: 649 AN: 2112

Alfa AF: 0.377 Hom.: 34677

Bravo AF: 0.316

Asia WGS AF: 0.177 AC: 617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.45
DANN	Benign	0.77
PhyloP100		-0.086
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: rs851982; hg19: chr6-152024985; COSMIC: COSV68605769;