rs851987

Variant names:

• chr6-151686754-A-G
• rs851987
• ENST00000473497.5:n.74-15121A>G

Variant summary

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

The ENST00000473497.5(ESR1):​n.74-15121A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 151,872 control chromosomes in the GnomAD database, including 33,215 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 0.66 (33215 hom., cov: 31)
• Consequence: ESR1 ENST00000473497.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.452
• Publications: 4 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

ENSG00000294140 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001385568.1	c.-201-15121A>G		intron_variant	Intron 1 of 9		NP_001372497.1
ESR1	XM_017010377.2	c.-201-15121A>G		intron_variant	Intron 2 of 10		XP_016865866.1
ESR1	XM_017010380.2	c.-71+29991A>G		intron_variant	Intron 1 of 8		XP_016865869.1
ESR1	XM_047418290.1	c.-201-15121A>G		intron_variant	Intron 1 of 9		XP_047274246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000473497.5	n.74-15121A>G		intron_variant	Intron 1 of 2	1
ENSG00000294140	ENST00000721398.1	n.86-835A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99895 AN: 151754 Hom.: 33199 Cov.: 31

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.672

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.658 AC: 99955 AN: 151872 Hom.: 33215 Cov.: 31 AF XY: 0.659 AC XY: 48913 AN XY: 74234

African (AFR) AF: 0.586 AC: 24238 AN: 41366

American (AMR) AF: 0.576 AC: 8808 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 2514 AN: 3464

East Asian (EAS) AF: 0.604 AC: 3106 AN: 5146

South Asian (SAS) AF: 0.671 AC: 3224 AN: 4802

European-Finnish (FIN) AF: 0.740 AC: 7802 AN: 10542

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 47999 AN: 67942

Other (OTH) AF: 0.674 AC: 1424 AN: 2114

Alfa AF: 0.684 Hom.: 45692

Bravo AF: 0.638

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.5
DANN	Benign	0.79
PhyloP100		-0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs851987; hg19: chr6-152007889; COSMIC: COSV68604070;