rs3020384

Variant names:

• chr6-152098055-C-G
• rs3020384
• NM_000125.4:c.1554-677C>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.1554-677C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,808 control chromosomes in the GnomAD database, including 9,852 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 0.33 (9852 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.127
• Publications: 3 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 (AFR) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1554-677C>G		intron_variant	Intron 7 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1554-677C>G		intron_variant	Intron 7 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50672 AN: 151690 Hom.: 9828 Cov.: 31

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.328

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

GnomAD4 genome AF: 0.334 AC: 50741 AN: 151808 Hom.: 9852 Cov.: 31 AF XY: 0.330 AC XY: 24501 AN XY: 74196

African (AFR) AF: 0.546 AC: 22570 AN: 41346

American (AMR) AF: 0.293 AC: 4477 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3470

East Asian (EAS) AF: 0.185 AC: 948 AN: 5134

South Asian (SAS) AF: 0.208 AC: 996 AN: 4798

European-Finnish (FIN) AF: 0.250 AC: 2643 AN: 10556

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17383 AN: 67926

Other (OTH) AF: 0.327 AC: 685 AN: 2098

Alfa AF: 0.317 Hom.: 1060

Bravo AF: 0.345

Asia WGS AF: 0.242 AC: 842 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	0.98
DANN	Benign	0.53
PhyloP100		-0.13
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: rs3020384; hg19: chr6-152419190;