rs3020375

Variant names:

• chr6-152068833-A-C
• rs3020375
• NM_000125.4:c.1369+7709A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-152068833-A-C
• chr6-152068833-A-T

Variant summary

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

The NM_000125.4(ESR1):​c.1369+7709A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 150,410 control chromosomes in the GnomAD database, including 17,984 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 0.46 (17984 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 19 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1369+7709A>C		intron_variant	Intron 6 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1369+7709A>C		intron_variant	Intron 6 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.456 AC: 68598 AN: 150296 Hom.: 17943 Cov.: 31

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.333

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.413

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

GnomAD4 genome AF: 0.457 AC: 68697 AN: 150410 Hom.: 17984 Cov.: 31 AF XY: 0.459 AC XY: 33682 AN XY: 73446

African (AFR) AF: 0.715 AC: 29044 AN: 40624

American (AMR) AF: 0.267 AC: 4074 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 971 AN: 3458

East Asian (EAS) AF: 0.579 AC: 2913 AN: 5028

South Asian (SAS) AF: 0.575 AC: 2697 AN: 4692

European-Finnish (FIN) AF: 0.447 AC: 4662 AN: 10424

Middle Eastern (MID) AF: 0.345 AC: 100 AN: 290

European-Non Finnish (NFE) AF: 0.341 AC: 23048 AN: 67672

Other (OTH) AF: 0.416 AC: 867 AN: 2084

Alfa AF: 0.364 Hom.: 19225

Bravo AF: 0.454

Asia WGS AF: 0.584 AC: 2030 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.27
DANN	Benign	0.49
PhyloP100		-1.4
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: rs3020375; hg19: chr6-152389968; COSMIC: COSV52801232;