6-151789808-T-G

Variant names:

• chr6-151789808-T-G
• rs543650
• ENST00000404742.5:c.-70-18035T>G

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-18035T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 151,528 control chromosomes in the GnomAD database, including 31,845 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 0.64 (31845 hom., cov: 32)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.657
• Publications: 52 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 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.-70-18035T>G		intron	N/A	NP_001116214.1
	ESR1	NM_001385568.1		c.-70-18035T>G		intron	N/A	NP_001372497.1
	ESR1	NM_001385570.1		c.-70-18035T>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.-70-18035T>G		intron	N/A	ENSP00000385373.1
	ESR1	ENST00000473497.5	TSL:1	n.205-18035T>G		intron	N/A
	ESR1	ENST00000440973.5	TSL:5	c.-70-18035T>G		intron	N/A	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97494 AN: 151412 Hom.: 31814 Cov.: 32

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.627

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

GnomAD4 genome AF: 0.644 AC: 97584 AN: 151528 Hom.: 31845 Cov.: 32 AF XY: 0.639 AC XY: 47313 AN XY: 74040

African (AFR) AF: 0.756 AC: 31171 AN: 41258

American (AMR) AF: 0.650 AC: 9910 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2148 AN: 3468

East Asian (EAS) AF: 0.569 AC: 2926 AN: 5138

South Asian (SAS) AF: 0.658 AC: 3161 AN: 4806

European-Finnish (FIN) AF: 0.518 AC: 5438 AN: 10506

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40785 AN: 67804

Other (OTH) AF: 0.628 AC: 1317 AN: 2098

Alfa AF: 0.617 Hom.: 128523

Bravo AF: 0.655

Asia WGS AF: 0.634 AC: 2202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.52
DANN	Benign	0.47
PhyloP100		-0.66
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: rs543650; hg19: chr6-152110943;