rs1999805

Variant names:

• chr6-151747229-G-A
• rs1999805
• ENST00000404742.5:c.-71+45224G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-151747229-G-A
• chr6-151747229-G-C
• chr6-151747229-G-T

Variant summary

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

The ENST00000404742.5(ESR1):​c.-71+45224G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 152,040 control chromosomes in the GnomAD database, including 23,056 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 0.54 (23056 hom., cov: 33)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639
• Publications: 63 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

LOC107986529 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC107986529	XR_001743866.2	n.9027C>T		non_coding_transcript_exon_variant	Exon 2 of 2
LOC107986529	XR_007059818.1	n.8960C>T		non_coding_transcript_exon_variant	Exon 2 of 2
ESR1	NM_001122742.2	c.-71+45224G>A		intron_variant	Intron 2 of 9		NP_001116214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000404742.5	c.-71+45224G>A		intron_variant	Intron 2 of 2	1		ENSP00000385373.1
ESR1	ENST00000473497.5	n.204+45224G>A		intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5	c.-71+45224G>A		intron_variant	Intron 2 of 9	5		ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82709 AN: 151922 Hom.: 23055 Cov.: 33

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.498

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

GnomAD4 genome AF: 0.544 AC: 82742 AN: 152040 Hom.: 23056 Cov.: 33 AF XY: 0.544 AC XY: 40401 AN XY: 74310

African (AFR) AF: 0.534 AC: 22151 AN: 41482

American (AMR) AF: 0.483 AC: 7385 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1928 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1407 AN: 5156

South Asian (SAS) AF: 0.387 AC: 1865 AN: 4820

European-Finnish (FIN) AF: 0.670 AC: 7073 AN: 10560

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39167 AN: 67960

Other (OTH) AF: 0.496 AC: 1048 AN: 2112

Alfa AF: 0.552 Hom.: 106114

Bravo AF: 0.528

Asia WGS AF: 0.347 AC: 1211 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.64
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: rs1999805; hg19: chr6-152068364; COSMIC: COSV68604360;