rs12204714

Variant names:

• chr6-151914204-C-T
• rs12204714
• NM_000125.4:c.761-29969C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000125.4(ESR1):​c.761-29969C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 151,350 control chromosomes in the GnomAD database, including 22,311 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 (22311 hom., cov: 30)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 9 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.761-29969C>T		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.761-29969C>T		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78119 AN: 151232 Hom.: 22318 Cov.: 30

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.559

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

GnomAD4 genome AF: 0.516 AC: 78129 AN: 151350 Hom.: 22311 Cov.: 30 AF XY: 0.511 AC XY: 37722 AN XY: 73880

African (AFR) AF: 0.294 AC: 12112 AN: 41234

American (AMR) AF: 0.488 AC: 7429 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2555 AN: 3466

East Asian (EAS) AF: 0.226 AC: 1163 AN: 5136

South Asian (SAS) AF: 0.381 AC: 1835 AN: 4810

European-Finnish (FIN) AF: 0.619 AC: 6400 AN: 10332

Middle Eastern (MID) AF: 0.728 AC: 211 AN: 290

European-Non Finnish (NFE) AF: 0.657 AC: 44561 AN: 67854

Other (OTH) AF: 0.554 AC: 1165 AN: 2102

Alfa AF: 0.581 Hom.: 6342

Bravo AF: 0.494

Asia WGS AF: 0.311 AC: 1083 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.69
PhyloP100		1.4
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: rs12204714; hg19: chr6-152235339;