chr6-152022628-A-G

Variant names:

• chr6-152022628-A-G
• rs3020411
• NM_000125.4:c.1235+10834A>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.1235+10834A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,822 control chromosomes in the GnomAD database, including 16,664 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 0.44 (16664 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.733
• Publications: 12 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=-0.61).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1235+10834A>G		intron_variant	Intron 5 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1235+10834A>G		intron_variant	Intron 5 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66758 AN: 151704 Hom.: 16628 Cov.: 31

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.404

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

GnomAD4 genome AF: 0.440 AC: 66849 AN: 151822 Hom.: 16664 Cov.: 31 AF XY: 0.441 AC XY: 32710 AN XY: 74174

African (AFR) AF: 0.672 AC: 27805 AN: 41368

American (AMR) AF: 0.261 AC: 3974 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 955 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3051 AN: 5130

South Asian (SAS) AF: 0.555 AC: 2663 AN: 4802

European-Finnish (FIN) AF: 0.401 AC: 4224 AN: 10538

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.337 AC: 22894 AN: 67952

Other (OTH) AF: 0.405 AC: 853 AN: 2106

Alfa AF: 0.361 Hom.: 8725

Bravo AF: 0.435

Asia WGS AF: 0.579 AC: 2015 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		0.73
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: rs3020411; hg19: chr6-152343763;