rs9478244

Variant names:

• chr6-151800902-A-G
• rs9478244
• ENST00000404742.5:c.-70-6941A>G

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-6941A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 151,936 control chromosomes in the GnomAD database, including 12,104 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 0.35 (12104 hom., cov: 31)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.935
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001122742.2	c.-70-6941A>G		intron_variant	Intron 2 of 9		NP_001116214.1
ESR1	NM_001385568.1	c.-70-6941A>G		intron_variant	Intron 2 of 9		NP_001372497.1
ESR1	NM_001385570.1	c.-70-6941A>G		intron_variant	Intron 2 of 8		NP_001372499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000404742.5	c.-70-6941A>G		intron_variant	Intron 2 of 2	1		ENSP00000385373.1
ESR1	ENST00000473497.5	n.205-6941A>G		intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5	c.-70-6941A>G		intron_variant	Intron 2 of 9	5		ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52859 AN: 151818 Hom.: 12064 Cov.: 31

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.349 AC: 52970 AN: 151936 Hom.: 12104 Cov.: 31 AF XY: 0.350 AC XY: 25963 AN XY: 74244

African (AFR) AF: 0.640 AC: 26491 AN: 41418

American (AMR) AF: 0.376 AC: 5743 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 656 AN: 3472

East Asian (EAS) AF: 0.443 AC: 2288 AN: 5162

South Asian (SAS) AF: 0.316 AC: 1520 AN: 4814

European-Finnish (FIN) AF: 0.223 AC: 2352 AN: 10546

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13047 AN: 67954

Other (OTH) AF: 0.319 AC: 673 AN: 2108

Alfa AF: 0.339 Hom.: 1788

Bravo AF: 0.373

Asia WGS AF: 0.406 AC: 1409 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.94
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: rs9478244; hg19: chr6-152122037;