rs1709181

chr6-151854045-T-Cchr6-151854045-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.643+11258T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,982 control chromosomes in the GnomAD database, including 17,632 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 0.47 (17632 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.277

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.643+11258T>C		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.643+11258T>C		intron_variant		1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71180 AN: 151866 Hom.: 17600 Cov.: 32

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.456

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

GnomAD4 genome AF: 0.469 AC: 71264 AN: 151982 Hom.: 17632 Cov.: 32 AF XY: 0.461 AC XY: 34247 AN XY: 74270

Gnomad4 AFR AF: 0.641

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.463

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.413

Gnomad4 OTH AF: 0.458

Alfa AF: 0.443 Hom.: 1902

Bravo AF: 0.480

Asia WGS AF: 0.471 AC: 1639 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	7.0
Dann	Benign	0.42

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: rs1709181; hg19: chr6-152175180; COSMIC: COSV52800712;