6-151906286-C-A

Variant names:

• chr6-151906286-C-A
• rs2347923
• NM_000125.4:c.760+25515C>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+25515C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 151,720 control chromosomes in the GnomAD database, including 29,929 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 0.62 (29929 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.200
• Publications: 16 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 (NFE) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.760+25515C>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+25515C>A		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94411 AN: 151600 Hom.: 29913 Cov.: 31

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.636

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

GnomAD4 genome AF: 0.623 AC: 94478 AN: 151720 Hom.: 29929 Cov.: 31 AF XY: 0.616 AC XY: 45641 AN XY: 74124

African (AFR) AF: 0.573 AC: 23685 AN: 41342

American (AMR) AF: 0.536 AC: 8170 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2654 AN: 3466

East Asian (EAS) AF: 0.404 AC: 2083 AN: 5156

South Asian (SAS) AF: 0.475 AC: 2285 AN: 4812

European-Finnish (FIN) AF: 0.665 AC: 6975 AN: 10496

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46355 AN: 67886

Other (OTH) AF: 0.634 AC: 1339 AN: 2112

Alfa AF: 0.667 Hom.: 4412

Bravo AF: 0.609

Asia WGS AF: 0.463 AC: 1608 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.80
DANN	Benign	0.19
PhyloP100		-0.20
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: rs2347923; hg19: chr6-152227421;