rs851982

Positions:

• chr6-151703850-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000404742.5(ESR1):​c.-71+1845T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 152,002 control chromosomes in the GnomAD database, including 8,955 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 0.33 (8955 hom., cov: 32)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_001122742.2	c.-71+1845T>C		intron_variant			NP_001116214.1
ESR1	NM_001385568.1	c.-71+1845T>C		intron_variant			NP_001372497.1
ESR1	NM_001385570.1	c.-71+1845T>C		intron_variant			NP_001372499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000404742.5	c.-71+1845T>C		intron_variant		1		ENSP00000385373
ESR1	ENST00000473497.5	n.204+1845T>C		intron_variant, non_coding_transcript_variant		1
ESR1	ENST00000440973.5	c.-71+1845T>C		intron_variant		5		ENSP00000405330	P1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50194 AN: 151884 Hom.: 8957 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.330 AC: 50208 AN: 152002 Hom.: 8955 Cov.: 32 AF XY: 0.328 AC XY: 24396 AN XY: 74312

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.448

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.307

Alfa AF: 0.381 Hom.: 16091

Bravo AF: 0.316

Asia WGS AF: 0.177 AC: 617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.45
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs851982; hg19: chr6-152024985; COSMIC: COSV68605769;