rs4870056

Variant names:

• chr6-151841092-G-A
• rs4870056
• NM_000125.4:c.453-1505G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-151841092-G-A
• chr6-151841092-G-T

Variant summary

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

The NM_000125.4(ESR1):​c.453-1505G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 152,012 control chromosomes in the GnomAD database, including 15,554 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 0.45 (15554 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.571
• Publications: 17 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.453-1505G>A		intron_variant	Intron 1 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.453-1505G>A		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68060 AN: 151892 Hom.: 15544 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.442

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.429

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

GnomAD4 genome AF: 0.448 AC: 68114 AN: 152012 Hom.: 15554 Cov.: 32 AF XY: 0.441 AC XY: 32765 AN XY: 74278

African (AFR) AF: 0.491 AC: 20367 AN: 41464

American (AMR) AF: 0.342 AC: 5223 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1533 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1870 AN: 5164

South Asian (SAS) AF: 0.428 AC: 2057 AN: 4810

European-Finnish (FIN) AF: 0.399 AC: 4209 AN: 10548

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.461 AC: 31357 AN: 67968

Other (OTH) AF: 0.429 AC: 907 AN: 2116

Alfa AF: 0.456 Hom.: 7133

Bravo AF: 0.442

Asia WGS AF: 0.395 AC: 1371 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.22
DANN	Benign	0.18
PhyloP100		-0.57
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: rs4870056; hg19: chr6-152162227;