rs3020401

Variant names:

• chr6-151961909-G-A
• rs3020401
• NM_000125.4:c.1096+17401G>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+17401G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 151,976 control chromosomes in the GnomAD database, including 25,637 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 0.56 (25637 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.664
• Publications: 18 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1096+17401G>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+17401G>A		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85258 AN: 151860 Hom.: 25636 Cov.: 31

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.561 AC: 85282 AN: 151976 Hom.: 25637 Cov.: 31 AF XY: 0.558 AC XY: 41415 AN XY: 74274

African (AFR) AF: 0.354 AC: 14676 AN: 41418

American (AMR) AF: 0.562 AC: 8584 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 2298 AN: 3464

East Asian (EAS) AF: 0.389 AC: 2000 AN: 5142

South Asian (SAS) AF: 0.432 AC: 2082 AN: 4820

European-Finnish (FIN) AF: 0.667 AC: 7051 AN: 10564

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46460 AN: 67968

Other (OTH) AF: 0.598 AC: 1266 AN: 2116

Alfa AF: 0.641 Hom.: 124571

Bravo AF: 0.542

Asia WGS AF: 0.415 AC: 1446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.68
DANN	Benign	0.76
PhyloP100		-0.66
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: rs3020401; hg19: chr6-152283044;