rs2982554

Variant names:

• chr6-151736875-A-C
• rs2982554
• ENST00000404742.5:c.-71+34870A>C

Variant summary

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

The ENST00000404742.5(ESR1):​c.-71+34870A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 151,834 control chromosomes in the GnomAD database, including 19,566 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 0.49 (19566 hom., cov: 31)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255
• Publications: 12 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=-0.93).
• 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
ESR1	NM_001122742.2	c.-71+34870A>C		intron_variant	Intron 2 of 9		NP_001116214.1
ESR1	NM_001385568.1	c.-71+34870A>C		intron_variant	Intron 2 of 9		NP_001372497.1
ESR1	NM_001385570.1	c.-71+34870A>C		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.-71+34870A>C		intron_variant	Intron 2 of 2	1		ENSP00000385373.1
ESR1	ENST00000473497.5	n.204+34870A>C		intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5	c.-71+34870A>C		intron_variant	Intron 2 of 9	5		ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74454 AN: 151716 Hom.: 19565 Cov.: 31

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.460

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

GnomAD4 genome AF: 0.491 AC: 74475 AN: 151834 Hom.: 19566 Cov.: 31 AF XY: 0.493 AC XY: 36605 AN XY: 74214

African (AFR) AF: 0.333 AC: 13786 AN: 41374

American (AMR) AF: 0.492 AC: 7508 AN: 15248

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

East Asian (EAS) AF: 0.231 AC: 1190 AN: 5160

South Asian (SAS) AF: 0.406 AC: 1954 AN: 4808

European-Finnish (FIN) AF: 0.695 AC: 7323 AN: 10534

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39102 AN: 67936

Other (OTH) AF: 0.459 AC: 965 AN: 2104

Alfa AF: 0.523 Hom.: 4673

Bravo AF: 0.466

Asia WGS AF: 0.343 AC: 1196 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		-0.26
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: rs2982554; hg19: chr6-152058010;