rs1856057

Variant names:

• chr6-151746734-A-G
• rs1856057
• ENST00000404742.5:c.-71+44729A>G

Variant summary

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

The ENST00000404742.5(ESR1):​c.-71+44729A>G 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 152,078 control chromosomes in the GnomAD database, including 23,055 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 (23055 hom., cov: 33)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.721
• Publications: 14 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC107986529	XR_001743866.2	n.9522T>C		non_coding_transcript_exon_variant	Exon 2 of 2
LOC107986529	XR_007059818.1	n.9455T>C		non_coding_transcript_exon_variant	Exon 2 of 2
ESR1	NM_001122742.2	c.-71+44729A>G		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+44729A>G		intron_variant	Intron 2 of 2	1		ENSP00000385373.1
ESR1	ENST00000473497.5	n.204+44729A>G		intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5	c.-71+44729A>G		intron_variant	Intron 2 of 9	5		ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82716 AN: 151960 Hom.: 23054 Cov.: 33

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.544 AC: 82749 AN: 152078 Hom.: 23055 Cov.: 33 AF XY: 0.543 AC XY: 40374 AN XY: 74322

African (AFR) AF: 0.534 AC: 22147 AN: 41476

American (AMR) AF: 0.484 AC: 7392 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1930 AN: 3470

East Asian (EAS) AF: 0.272 AC: 1408 AN: 5168

South Asian (SAS) AF: 0.386 AC: 1858 AN: 4812

European-Finnish (FIN) AF: 0.669 AC: 7084 AN: 10588

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

European-Non Finnish (NFE) AF: 0.576 AC: 39166 AN: 67964

Other (OTH) AF: 0.497 AC: 1049 AN: 2112

Alfa AF: 0.550 Hom.: 10432

Bravo AF: 0.528

Asia WGS AF: 0.347 AC: 1213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.64
DANN	Benign	0.81
PhyloP100		-0.72
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: rs1856057; hg19: chr6-152067869; COSMIC: COSV68604357;