NM_000125.4:c.1096+825G>A

Variant names:

• chr6-151945333-G-A
• rs3003917
• NM_000125.4:c.1096+825G>A

Variant summary

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

The NM_000125.4(ESR1):​c.1096+825G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 152,178 control chromosomes in the GnomAD database, including 41,109 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 0.73 (41109 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 13 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1096+825G>A		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.1096+825G>A		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110501 AN: 152060 Hom.: 41096 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.760

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

GnomAD4 genome AF: 0.726 AC: 110548 AN: 152178 Hom.: 41109 Cov.: 33 AF XY: 0.719 AC XY: 53463 AN XY: 74406

African (AFR) AF: 0.648 AC: 26887 AN: 41496

American (AMR) AF: 0.738 AC: 11288 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2825 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1597 AN: 5178

South Asian (SAS) AF: 0.562 AC: 2712 AN: 4826

European-Finnish (FIN) AF: 0.730 AC: 7712 AN: 10568

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.807 AC: 54895 AN: 68024

Other (OTH) AF: 0.753 AC: 1588 AN: 2110

Alfa AF: 0.786 Hom.: 73639

Bravo AF: 0.723

Asia WGS AF: 0.456 AC: 1587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.6
DANN	Benign	0.67
PhyloP100		1.1
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: rs3003917; hg19: chr6-152266468;