6-151661278-C-T

Variant names:

• chr6-151661278-C-T
• rs866457
• ENST00000473497.5:n.73+4515C>T

Variant summary

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

The ENST00000473497.5(ESR1):​n.73+4515C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 151,974 control chromosomes in the GnomAD database, including 23,705 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 0.55 (23705 hom., cov: 32)
• Consequence: ESR1 ENST00000473497.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.18
• Publications: 4 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000473497.5. 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_001385568.1		c.-202+4515C>T		intron	N/A	NP_001372497.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000473497.5	TSL:1	n.73+4515C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82862 AN: 151856 Hom.: 23669 Cov.: 32

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.523

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

GnomAD4 genome AF: 0.546 AC: 82960 AN: 151974 Hom.: 23705 Cov.: 32 AF XY: 0.547 AC XY: 40625 AN XY: 74276

African (AFR) AF: 0.710 AC: 29418 AN: 41434

American (AMR) AF: 0.514 AC: 7845 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1873 AN: 3468

East Asian (EAS) AF: 0.781 AC: 4027 AN: 5158

South Asian (SAS) AF: 0.536 AC: 2586 AN: 4824

European-Finnish (FIN) AF: 0.452 AC: 4760 AN: 10538

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30845 AN: 67966

Other (OTH) AF: 0.527 AC: 1111 AN: 2110

Alfa AF: 0.476 Hom.: 14763

Bravo AF: 0.557

Asia WGS AF: 0.674 AC: 2342 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.053
DANN	Benign	0.40
PhyloP100		-2.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs866457; hg19: chr6-151982413;