NM_000125.4:c.452+1419A>G

Variant names:

• chr6-151809783-A-G
• rs532010
• NM_000125.4:c.452+1419A>G

Variant summary

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

The NM_000125.4(ESR1):​c.452+1419A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,998 control chromosomes in the GnomAD database, including 12,009 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 0.40 (12009 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.622
• Publications: 30 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=-0.77).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.452+1419A>G		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.452+1419A>G		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60418 AN: 151880 Hom.: 12005 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.398 AC: 60442 AN: 151998 Hom.: 12009 Cov.: 32 AF XY: 0.394 AC XY: 29304 AN XY: 74284

African (AFR) AF: 0.424 AC: 17578 AN: 41440

American (AMR) AF: 0.431 AC: 6574 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1544 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1965 AN: 5176

South Asian (SAS) AF: 0.461 AC: 2216 AN: 4806

European-Finnish (FIN) AF: 0.284 AC: 3002 AN: 10566

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26318 AN: 67962

Other (OTH) AF: 0.400 AC: 844 AN: 2108

Alfa AF: 0.394 Hom.: 23589

Bravo AF: 0.405

Asia WGS AF: 0.426 AC: 1479 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs532010; hg19: chr6-152130918; COSMIC: COSV52800676; COSMIC: COSV52800676;