rs3841686

Positions:

• chr6-152060952-C-CT
• chr6-152060952-C-CTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000125.4(ESR1):​c.1236-34dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,499,170 control chromosomes in the GnomAD database, including 9,048 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1210 hom., cov: 31)
  • Exomes 𝑓: 0.095 (7838 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.330

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.1236-34dup		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.1236-34dup		intron_variant		1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17039 AN: 151708 Hom.: 1211 Cov.: 31

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0645

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.119 AC: 18298 AN: 153482 Hom.: 1605 AF XY: 0.122 AC XY: 9941 AN XY: 81484

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0396

Gnomad ASJ exome AF: 0.0998

Gnomad EAS exome AF: 0.346

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.0834

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0952 AC: 128286 AN: 1347344 Hom.: 7838 Cov.: 24 AF XY: 0.0973 AC XY: 64902 AN XY: 666848

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.0427

Gnomad4 ASJ exome AF: 0.0984

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.0794

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.112 AC: 17050 AN: 151826 Hom.: 1210 Cov.: 31 AF XY: 0.117 AC XY: 8676 AN XY: 74198

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0642

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.0822

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0929 Hom.: 122

Bravo AF: 0.103

Asia WGS AF: 0.236 AC: 819 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs3841686; hg19: chr6-152382087;