ENST00000427531.6:c.851-17697C>G

Variant names:

• chr6-152107569-C-G
• rs1543403
• ENST00000427531.6:c.851-17697C>G

Variant summary

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

The ENST00000427531.6(ESR1):​c.851-17697C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 151,990 control chromosomes in the GnomAD database, including 18,807 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 0.50 (18807 hom., cov: 33)
• Consequence: ESR1 ENST00000427531.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 15 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

ENSG00000298278 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001328100.2	c.851-17697C>G		intron_variant	Intron 6 of 6		NP_001315029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000427531.6	c.851-17697C>G		intron_variant	Intron 6 of 6	1		ENSP00000394721.2
ESR1	ENST00000641399.1	n.1070+8649C>G		intron_variant	Intron 6 of 6
ENSG00000298278	ENST00000754431.1	n.320+1972G>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75173 AN: 151872 Hom.: 18788 Cov.: 33

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.469

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

GnomAD4 genome AF: 0.495 AC: 75248 AN: 151990 Hom.: 18807 Cov.: 33 AF XY: 0.499 AC XY: 37057 AN XY: 74294

African (AFR) AF: 0.526 AC: 21805 AN: 41446

American (AMR) AF: 0.464 AC: 7073 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1523 AN: 3466

East Asian (EAS) AF: 0.560 AC: 2893 AN: 5168

South Asian (SAS) AF: 0.466 AC: 2246 AN: 4822

European-Finnish (FIN) AF: 0.632 AC: 6666 AN: 10548

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31582 AN: 67972

Other (OTH) AF: 0.468 AC: 987 AN: 2108

Alfa AF: 0.483 Hom.: 2161

Bravo AF: 0.481

Asia WGS AF: 0.545 AC: 1900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.11
DANN	Benign	0.34
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1543403; hg19: chr6-152428704; COSMIC: COSV52785523; COSMIC: COSV52785523;