rs3853251

chr6-151839621-A-Gchr6-151839621-A-T

Variant summary

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

The NM_000125.4(ESR1):c.453-2976A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,212 control chromosomes in the GnomAD database, including 5,494 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 0.25 (5494 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.487

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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.453-2976A>G		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.453-2976A>G		intron_variant		1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38501 AN: 152094 Hom.: 5499 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.266

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

GnomAD4 genome AF: 0.253 AC: 38507 AN: 152212 Hom.: 5494 Cov.: 32 AF XY: 0.245 AC XY: 18218 AN XY: 74410

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.262

Alfa AF: 0.281 Hom.: 778

Bravo AF: 0.250

Asia WGS AF: 0.125 AC: 436 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	1.8
Dann	Benign	0.54

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: rs3853251; hg19: chr6-152160756; COSMIC: COSV52800683;