NM_000125.4:c.453-17011T>C

Variant names:

• chr6-151825586-T-C
• rs3866461
• NM_000125.4:c.453-17011T>C

Variant summary

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

The NM_000125.4(ESR1):​c.453-17011T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 151,916 control chromosomes in the GnomAD database, including 4,892 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 0.23 (4892 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.453-17011T>C		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.453-17011T>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.453-17011T>C		intron	N/A	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.453-17011T>C		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+17222T>C		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.-68+16315T>C		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34320 AN: 151796 Hom.: 4876 Cov.: 31

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.226 AC: 34377 AN: 151916 Hom.: 4892 Cov.: 31 AF XY: 0.229 AC XY: 16976 AN XY: 74246

African (AFR) AF: 0.406 AC: 16827 AN: 41396

American (AMR) AF: 0.238 AC: 3632 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 516 AN: 3466

East Asian (EAS) AF: 0.292 AC: 1503 AN: 5140

South Asian (SAS) AF: 0.220 AC: 1057 AN: 4810

European-Finnish (FIN) AF: 0.162 AC: 1711 AN: 10562

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8536 AN: 67964

Other (OTH) AF: 0.213 AC: 450 AN: 2112

Alfa AF: 0.115 Hom.: 262

Bravo AF: 0.237

Asia WGS AF: 0.292 AC: 1015 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.025
DANN	Benign	0.53
PhyloP100		-2.1
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: rs3866461; hg19: chr6-152146721;