rs726282

Variant names:

• chr6-151981519-A-C
• rs726282
• NM_000125.4:c.1097-30137A>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.1097-30137A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 152,222 control chromosomes in the GnomAD database, including 60,841 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 0.89 (60841 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1097-30137A>C		intron_variant	Intron 4 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1097-30137A>C		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135603 AN: 152104 Hom.: 60804 Cov.: 33

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.914

Gnomad ASJ AF: 0.927

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.903

Gnomad OTH AF: 0.895

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

GnomAD4 genome AF: 0.891 AC: 135700 AN: 152222 Hom.: 60841 Cov.: 33 AF XY: 0.886 AC XY: 65935 AN XY: 74406

African (AFR) AF: 0.927 AC: 38499 AN: 41546

American (AMR) AF: 0.914 AC: 13978 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.927 AC: 3218 AN: 3470

East Asian (EAS) AF: 0.616 AC: 3186 AN: 5174

South Asian (SAS) AF: 0.769 AC: 3710 AN: 4824

European-Finnish (FIN) AF: 0.821 AC: 8687 AN: 10584

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.903 AC: 61432 AN: 68010

Other (OTH) AF: 0.892 AC: 1885 AN: 2114

Alfa AF: 0.907 Hom.: 17999

Bravo AF: 0.900

Asia WGS AF: 0.702 AC: 2440 AN: 3472

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	0.69
PhyloP100		-0.54
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: rs726282; hg19: chr6-152302654;