rs2347867

Variant names:

• chr6-151908715-G-A
• rs2347867
• NM_000125.4:c.760+27944G>A

Variant summary

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

The NM_000125.4(ESR1):​c.760+27944G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 151,862 control chromosomes in the GnomAD database, including 22,803 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 0.52 (22803 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.548
• Publications: 32 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.760+27944G>A		intron_variant	Intron 3 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.760+27944G>A		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79414 AN: 151742 Hom.: 22805 Cov.: 31

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.729

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.568

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

GnomAD4 genome AF: 0.523 AC: 79439 AN: 151862 Hom.: 22803 Cov.: 31 AF XY: 0.518 AC XY: 38438 AN XY: 74252

African (AFR) AF: 0.311 AC: 12853 AN: 41382

American (AMR) AF: 0.495 AC: 7553 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2577 AN: 3468

East Asian (EAS) AF: 0.227 AC: 1170 AN: 5164

South Asian (SAS) AF: 0.383 AC: 1844 AN: 4810

European-Finnish (FIN) AF: 0.629 AC: 6631 AN: 10538

Middle Eastern (MID) AF: 0.743 AC: 217 AN: 292

European-Non Finnish (NFE) AF: 0.658 AC: 44706 AN: 67918

Other (OTH) AF: 0.563 AC: 1190 AN: 2112

Alfa AF: 0.609 Hom.: 81093

Bravo AF: 0.502

Asia WGS AF: 0.315 AC: 1099 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.068
DANN	Benign	0.19
PhyloP100		-0.55
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: rs2347867; hg19: chr6-152229850;