rs12154178

chr6-151929945-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000125.4(ESR1):c.761-14228C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 151,660 control chromosomes in the GnomAD database, including 27,203 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 0.59 (27203 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.761-14228C>A		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.761-14228C>A		intron_variant		1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88753 AN: 151546 Hom.: 27205 Cov.: 31

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.679

Gnomad MID AF: 0.739

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.609

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

GnomAD4 genome AF: 0.585 AC: 88790 AN: 151660 Hom.: 27203 Cov.: 31 AF XY: 0.581 AC XY: 43059 AN XY: 74132

Gnomad4 AFR AF: 0.426

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.736

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.478

Gnomad4 FIN AF: 0.679

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.607

Alfa AF: 0.670 Hom.: 57513

Bravo AF: 0.563

Asia WGS AF: 0.452 AC: 1577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	2.4
Dann	Benign	0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs12154178; hg19: chr6-152251080;