NM_000125.4:c.760+27539T>C

Variant names:

• chr6-151908310-T-C
• rs1514347
• NM_000125.4:c.760+27539T>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.760+27539T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 152,046 control chromosomes in the GnomAD database, including 46,183 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 0.77 (46183 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.39
• Publications: 12 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.760+27539T>C		intron_variant	Intron 3 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.760+27539T>C		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117742 AN: 151928 Hom.: 46148 Cov.: 31

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.803

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.782

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

GnomAD4 genome AF: 0.775 AC: 117831 AN: 152046 Hom.: 46183 Cov.: 31 AF XY: 0.767 AC XY: 56984 AN XY: 74282

African (AFR) AF: 0.871 AC: 36162 AN: 41510

American (AMR) AF: 0.727 AC: 11103 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2854 AN: 3468

East Asian (EAS) AF: 0.511 AC: 2641 AN: 5172

South Asian (SAS) AF: 0.609 AC: 2928 AN: 4808

European-Finnish (FIN) AF: 0.708 AC: 7462 AN: 10536

Middle Eastern (MID) AF: 0.822 AC: 240 AN: 292

European-Non Finnish (NFE) AF: 0.765 AC: 52017 AN: 67956

Other (OTH) AF: 0.778 AC: 1647 AN: 2116

Alfa AF: 0.772 Hom.: 18172

Bravo AF: 0.783

Asia WGS AF: 0.600 AC: 2090 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.065
DANN	Benign	0.35
PhyloP100		-2.4
Mutation Taster		=97/3	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: rs1514347; hg19: chr6-152229445;