ENST00000404742.5:c.-70-39210C>A

Variant names:

• chr6-151768633-C-A
• rs2485209
• ENST00000404742.5:c.-70-39210C>A

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-39210C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 151,912 control chromosomes in the GnomAD database, including 30,218 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 0.63 (30218 hom., cov: 31)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 11 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001122742.2	c.-70-39210C>A		intron_variant	Intron 2 of 9		NP_001116214.1
ESR1	NM_001385568.1	c.-70-39210C>A		intron_variant	Intron 2 of 9		NP_001372497.1
ESR1	NM_001385570.1	c.-70-39210C>A		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.-70-39210C>A		intron_variant	Intron 2 of 2	1		ENSP00000385373.1
ESR1	ENST00000473497.5	n.205-39210C>A		intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5	c.-70-39210C>A		intron_variant	Intron 2 of 9	5		ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95064 AN: 151794 Hom.: 30193 Cov.: 31

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.571

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

GnomAD4 genome AF: 0.626 AC: 95126 AN: 151912 Hom.: 30218 Cov.: 31 AF XY: 0.630 AC XY: 46796 AN XY: 74230

African (AFR) AF: 0.715 AC: 29610 AN: 41414

American (AMR) AF: 0.526 AC: 8020 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1931 AN: 3466

East Asian (EAS) AF: 0.570 AC: 2941 AN: 5164

South Asian (SAS) AF: 0.618 AC: 2969 AN: 4806

European-Finnish (FIN) AF: 0.750 AC: 7916 AN: 10556

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.588 AC: 39955 AN: 67940

Other (OTH) AF: 0.569 AC: 1201 AN: 2110

Alfa AF: 0.585 Hom.: 51653

Bravo AF: 0.613

Asia WGS AF: 0.600 AC: 2087 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.4
DANN	Benign	0.50
PhyloP100		1.0
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: rs2485209; hg19: chr6-152089768; COSMIC: COSV68604389;