rs7749659

Positions:

• chr6-151723749-A-G

Variant summary

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

The ENST00000404742.5(ESR1):​c.-71+21744A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 151,552 control chromosomes in the GnomAD database, including 6,565 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 0.28 (6565 hom., cov: 32)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539

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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_001122742.2	c.-71+21744A>G		intron_variant			NP_001116214.1
ESR1	NM_001385568.1	c.-71+21744A>G		intron_variant			NP_001372497.1
ESR1	NM_001385570.1	c.-71+21744A>G		intron_variant			NP_001372499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000404742.5	c.-71+21744A>G		intron_variant		1		ENSP00000385373
ESR1	ENST00000473497.5	n.204+21744A>G		intron_variant, non_coding_transcript_variant		1
ESR1	ENST00000440973.5	c.-71+21744A>G		intron_variant		5		ENSP00000405330	P1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43047 AN: 151434 Hom.: 6555 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.238

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

GnomAD4 genome AF: 0.284 AC: 43097 AN: 151552 Hom.: 6565 Cov.: 32 AF XY: 0.282 AC XY: 20904 AN XY: 74058

Gnomad4 AFR AF: 0.401

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.153

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.236

Alfa AF: 0.281 Hom.: 775

Bravo AF: 0.287

Asia WGS AF: 0.163 AC: 569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.94
DANN	Benign	0.10

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: rs7749659; hg19: chr6-152044884; COSMIC: COSV68604218;