6-151795520-A-G

Variant names:

• chr6-151795520-A-G
• rs17081685
• ENST00000404742.5:c.-70-12323A>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.-70-12323A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 150,944 control chromosomes in the GnomAD database, including 1,910 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 0.13 (1910 hom., cov: 31)
• Consequence: ESR1 NM_001122742.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 10 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 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.-70-12323A>G		intron	N/A	NP_001116214.1	G4XH65
	ESR1	NM_001385568.1		c.-70-12323A>G		intron	N/A	NP_001372497.1	P03372-1
	ESR1	NM_001385570.1		c.-70-12323A>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.-70-12323A>G		intron	N/A	ENSP00000385373.1	Q5T5H8
	ESR1	ENST00000473497.5	TSL:1	n.205-12323A>G		intron	N/A
	ESR1	ENST00000440973.5	TSL:5	c.-70-12323A>G		intron	N/A	ENSP00000405330.1	P03372-1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20162 AN: 150842 Hom.: 1905 Cov.: 31

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0725

Gnomad OTH AF: 0.140

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

GnomAD4 genome AF: 0.134 AC: 20194 AN: 150944 Hom.: 1910 Cov.: 31 AF XY: 0.135 AC XY: 9964 AN XY: 73716

African (AFR) AF: 0.200 AC: 8180 AN: 40914

American (AMR) AF: 0.260 AC: 3926 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3468

East Asian (EAS) AF: 0.294 AC: 1484 AN: 5040

South Asian (SAS) AF: 0.118 AC: 565 AN: 4786

European-Finnish (FIN) AF: 0.0605 AC: 630 AN: 10418

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.0726 AC: 4929 AN: 67930

Other (OTH) AF: 0.143 AC: 300 AN: 2096

Alfa AF: 0.0979 Hom.: 4808

Bravo AF: 0.157

Asia WGS AF: 0.223 AC: 771 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.83
PhyloP100		1.0
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: rs17081685; hg19: chr6-152116655;