chr6-151804309-T-C

Variant names:

• chr6-151804309-T-C
• rs488133
• ENST00000404742.5:c.-70-3534T>C

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-3534T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 152,098 control chromosomes in the GnomAD database, including 46,037 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 0.77 (46025 hom., cov: 30)
  • Exomes 𝑓: 0.81 (12 hom.)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• Publications: 35 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 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.-70-3534T>C		intron	N/A	NP_001116214.1
	ESR1	NM_001385568.1		c.-70-3534T>C		intron	N/A	NP_001372497.1
	ESR1	NM_001385570.1		c.-70-3534T>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.-70-3534T>C		intron	N/A	ENSP00000385373.1
	ESR1	ENST00000473497.5	TSL:1	n.205-3534T>C		intron	N/A
	ESR1	ENST00000440973.5	TSL:5	c.-70-3534T>C		intron	N/A	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116754 AN: 151944 Hom.: 45970 Cov.: 30

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.748

GnomAD4 exome AF: 0.806 AC: 29 AN: 36 Hom.: 12 AF XY: 0.769 AC XY: 20 AN XY: 26

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.750 AC: 6 AN: 8

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.818 AC: 18 AN: 22

Other (OTH) AF: 1.00 AC: 2 AN: 2

GnomAD4 genome AF: 0.769 AC: 116869 AN: 152062 Hom.: 46025 Cov.: 30 AF XY: 0.771 AC XY: 57325 AN XY: 74314

African (AFR) AF: 0.939 AC: 38990 AN: 41520

American (AMR) AF: 0.777 AC: 11872 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2409 AN: 3470

East Asian (EAS) AF: 0.938 AC: 4833 AN: 5154

South Asian (SAS) AF: 0.780 AC: 3751 AN: 4810

European-Finnish (FIN) AF: 0.699 AC: 7366 AN: 10544

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45298 AN: 67960

Other (OTH) AF: 0.749 AC: 1584 AN: 2114

Alfa AF: 0.697 Hom.: 120926

Bravo AF: 0.779

Asia WGS AF: 0.859 AC: 2986 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.022
DANN	Benign	0.59
PhyloP100		-2.7
PromoterAI		0.017	Neutral
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: rs488133; hg19: chr6-152125444;