rs1033182

Variant names:

• chr6-151873899-G-A
• rs1033182
• NM_000125.4:c.644-6756G>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.644-6756G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,122 control chromosomes in the GnomAD database, including 6,367 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 0.26 (6367 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0790
• Publications: 6 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.644-6756G>A		intron_variant	Intron 2 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.644-6756G>A		intron_variant	Intron 2 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38937 AN: 152004 Hom.: 6373 Cov.: 32

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.274

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

GnomAD4 genome AF: 0.256 AC: 38926 AN: 152122 Hom.: 6367 Cov.: 32 AF XY: 0.248 AC XY: 18442 AN XY: 74354

African (AFR) AF: 0.0679 AC: 2820 AN: 41548

American (AMR) AF: 0.265 AC: 4040 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1387 AN: 3466

East Asian (EAS) AF: 0.0257 AC: 133 AN: 5180

South Asian (SAS) AF: 0.216 AC: 1044 AN: 4824

European-Finnish (FIN) AF: 0.260 AC: 2748 AN: 10556

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25746 AN: 67954

Other (OTH) AF: 0.271 AC: 572 AN: 2114

Alfa AF: 0.331 Hom.: 11883

Bravo AF: 0.248

Asia WGS AF: 0.127 AC: 442 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.82
PhyloP100		-0.079
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: rs1033182; hg19: chr6-152195034; COSMIC: COSV52800768;