6-151786801-A-G

Variant names:

• chr6-151786801-A-G
• rs12661437
• ENST00000404742.5:c.-70-21042A>G

Variant summary

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

The NM_001122742.2(ESR1):​c.-70-21042A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 151,736 control chromosomes in the GnomAD database, including 7,675 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 0.29 (7675 hom., cov: 31)
• Consequence: ESR1 NM_001122742.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 2 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 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.-70-21042A>G		intron	N/A	NP_001116214.1	G4XH65
	ESR1	NM_001385568.1		c.-70-21042A>G		intron	N/A	NP_001372497.1	P03372-1
	ESR1	NM_001385570.1		c.-70-21042A>G		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.-70-21042A>G		intron	N/A	ENSP00000385373.1	Q5T5H8
	ESR1	ENST00000473497.5	TSL:1	n.205-21042A>G		intron	N/A
	ESR1	ENST00000440973.5	TSL:5	c.-70-21042A>G		intron	N/A	ENSP00000405330.1	P03372-1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43505 AN: 151618 Hom.: 7659 Cov.: 31

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.258

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

GnomAD4 genome AF: 0.287 AC: 43587 AN: 151736 Hom.: 7675 Cov.: 31 AF XY: 0.287 AC XY: 21302 AN XY: 74116

African (AFR) AF: 0.488 AC: 20186 AN: 41376

American (AMR) AF: 0.346 AC: 5270 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3470

East Asian (EAS) AF: 0.334 AC: 1718 AN: 5150

South Asian (SAS) AF: 0.166 AC: 796 AN: 4802

European-Finnish (FIN) AF: 0.218 AC: 2284 AN: 10466

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12166 AN: 67910

Other (OTH) AF: 0.259 AC: 545 AN: 2106

Alfa AF: 0.182 Hom.: 1070

Bravo AF: 0.308

Asia WGS AF: 0.278 AC: 965 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.34
DANN	Benign	0.37
PhyloP100		-2.3
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: rs12661437; hg19: chr6-152107936;