rs4583998

Variant names:

• chr6-151939533-A-G
• rs4583998
• NM_000125.4:c.761-4640A>G

Variant summary

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

The NM_000125.4(ESR1):​c.761-4640A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 152,032 control chromosomes in the GnomAD database, including 27,584 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 0.59 (27584 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135
• Publications: 17 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 = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.761-4640A>G		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.761-4640A>G		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89684 AN: 151914 Hom.: 27585 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.613

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

GnomAD4 genome AF: 0.590 AC: 89724 AN: 152032 Hom.: 27584 Cov.: 32 AF XY: 0.585 AC XY: 43488 AN XY: 74324

African (AFR) AF: 0.442 AC: 18310 AN: 41438

American (AMR) AF: 0.534 AC: 8152 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2556 AN: 3472

East Asian (EAS) AF: 0.393 AC: 2038 AN: 5180

South Asian (SAS) AF: 0.477 AC: 2303 AN: 4824

European-Finnish (FIN) AF: 0.677 AC: 7148 AN: 10556

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 47005 AN: 67984

Other (OTH) AF: 0.610 AC: 1284 AN: 2104

Alfa AF: 0.651 Hom.: 91827

Bravo AF: 0.569

Asia WGS AF: 0.454 AC: 1581 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.1
DANN	Benign	0.69
PhyloP100		0.14
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: rs4583998; hg19: chr6-152260668;