6-151782657-T-C

Variant names:

• chr6-151782657-T-C
• rs1285057
• ENST00000404742.5:c.-70-25186T>C

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-25186T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 152,042 control chromosomes in the GnomAD database, including 34,416 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 0.67 (34416 hom., cov: 32)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.186
• Publications: 7 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.747 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.-70-25186T>C		intron	N/A	NP_001116214.1
	ESR1	NM_001385568.1		c.-70-25186T>C		intron	N/A	NP_001372497.1
	ESR1	NM_001385570.1		c.-70-25186T>C		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.-70-25186T>C		intron	N/A	ENSP00000385373.1
	ESR1	ENST00000473497.5	TSL:1	n.205-25186T>C		intron	N/A
	ESR1	ENST00000440973.5	TSL:5	c.-70-25186T>C		intron	N/A	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101550 AN: 151924 Hom.: 34374 Cov.: 32

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.636

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

GnomAD4 genome AF: 0.669 AC: 101645 AN: 152042 Hom.: 34416 Cov.: 32 AF XY: 0.671 AC XY: 49860 AN XY: 74342

African (AFR) AF: 0.754 AC: 31265 AN: 41480

American (AMR) AF: 0.575 AC: 8786 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1949 AN: 3468

East Asian (EAS) AF: 0.712 AC: 3669 AN: 5150

South Asian (SAS) AF: 0.579 AC: 2794 AN: 4822

European-Finnish (FIN) AF: 0.787 AC: 8315 AN: 10568

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42896 AN: 67964

Other (OTH) AF: 0.634 AC: 1338 AN: 2110

Alfa AF: 0.634 Hom.: 134273

Bravo AF: 0.659

Asia WGS AF: 0.620 AC: 2158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.1
DANN	Benign	0.49
PhyloP100		-0.19
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: rs1285057; hg19: chr6-152103792; COSMIC: COSV68603926;