6-151810964-T-G

Variant summary

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

The NM_000125.4(ESR1):c.452+2600T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,206 control chromosomes in the GnomAD database, including 2,433 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 0.15 (2433 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.165

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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.452+2600T>G		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.452+2600T>G		intron_variant		1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23097 AN: 152088 Hom.: 2425 Cov.: 33

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.0887

Gnomad EAS AF: 0.00615

Gnomad SAS AF: 0.0426

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.116

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.152 AC: 23146 AN: 152206 Hom.: 2433 Cov.: 33 AF XY: 0.149 AC XY: 11112 AN XY: 74444

Gnomad4 AFR AF: 0.291

Gnomad4 AMR AF: 0.0638

Gnomad4 ASJ AF: 0.0887

Gnomad4 EAS AF: 0.00617

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0666 Hom.: 77

Bravo AF: 0.152

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	9.6
Dann	Benign	0.79

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: rs17081698; hg19: chr6-152132099;