ENST00000404742.5:c.-70-9859T>G

Variant names:

• chr6-151797984-T-G
• rs2881766
• ENST00000404742.5:c.-70-9859T>G

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-9859T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,018 control chromosomes in the GnomAD database, including 12,102 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 0.35 (12102 hom., cov: 33)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107
• Publications: 23 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 (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000404742.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_001122742.2		c.-70-9859T>G		intron	N/A	NP_001116214.1
	ESR1	NM_001385568.1		c.-70-9859T>G		intron	N/A	NP_001372497.1
	ESR1	NM_001385570.1		c.-70-9859T>G		intron	N/A	NP_001372499.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000404742.5	TSL:1	c.-70-9859T>G		intron	N/A	ENSP00000385373.1
	ESR1	ENST00000473497.5	TSL:1	n.205-9859T>G		intron	N/A
	ESR1	ENST00000440973.5	TSL:5	c.-70-9859T>G		intron	N/A	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52902 AN: 151900 Hom.: 12063 Cov.: 33

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.317

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

GnomAD4 genome AF: 0.349 AC: 53011 AN: 152018 Hom.: 12102 Cov.: 33 AF XY: 0.350 AC XY: 25985 AN XY: 74306

African (AFR) AF: 0.639 AC: 26490 AN: 41444

American (AMR) AF: 0.376 AC: 5743 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 653 AN: 3464

East Asian (EAS) AF: 0.449 AC: 2318 AN: 5166

South Asian (SAS) AF: 0.316 AC: 1518 AN: 4810

European-Finnish (FIN) AF: 0.223 AC: 2359 AN: 10578

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13049 AN: 67946

Other (OTH) AF: 0.322 AC: 681 AN: 2116

Alfa AF: 0.241 Hom.: 23607

Bravo AF: 0.373

Asia WGS AF: 0.408 AC: 1416 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	1.9
DANN	Benign	0.60
PhyloP100		-0.11
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: rs2881766; hg19: chr6-152119119;