rs33986155

chr6-152099550-C-Gchr6-152099550-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000125.4(ESR1):c.*584C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 242,100 control chromosomes in the GnomAD database, including 204 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 0.034 (104 hom., cov: 32)
  • Exomes 𝑓: 0.042 (100 hom.)
• Consequence: ESR1 NM_000125.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359

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=-0.59).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0337 (5126/152208) while in subpopulation NFE AF= 0.0487 (3311/68006). AF 95% confidence interval is 0.0473. There are 104 homozygotes in gnomad4. There are 2414 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.*584C>G		3_prime_UTR_variant	8/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.*584C>G		3_prime_UTR_variant	8/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5131 AN: 152090 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.00927

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0487

Gnomad OTH AF: 0.0464

GnomAD4 exome AF: 0.0424 AC: 3808 AN: 89892 Hom.: 100 Cov.: 0 AF XY: 0.0432 AC XY: 1809 AN XY: 41832

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0346

Gnomad4 ASJ exome AF: 0.0874

Gnomad4 EAS exome AF: 0.0000847

Gnomad4 SAS exome AF: 0.0289

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0500

Gnomad4 OTH exome AF: 0.0459

GnomAD4 genome AF: 0.0337 AC: 5126 AN: 152208 Hom.: 104 Cov.: 32 AF XY: 0.0324 AC XY: 2414 AN XY: 74432

Gnomad4 AFR AF: 0.00922

Gnomad4 AMR AF: 0.0371

Gnomad4 ASJ AF: 0.0948

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0241

Gnomad4 FIN AF: 0.0273

Gnomad4 NFE AF: 0.0487

Gnomad4 OTH AF: 0.0454

Alfa AF: 0.0169 Hom.: 5

Bravo AF: 0.0335

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	5.3
Dann	Benign	0.76

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: rs33986155; hg19: chr6-152420685;