rs9478244

chr6-151800902-A-G

Variant summary

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

The ENST00000404742.5(ESR1):c.-70-6941A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 151,936 control chromosomes in the GnomAD database, including 12,104 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 0.35 (12104 hom., cov: 31)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.935

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_001122742.2	c.-70-6941A>G		intron_variant
ESR1	NM_001385568.1	c.-70-6941A>G		intron_variant
ESR1	NM_001385570.1	c.-70-6941A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000404742.5	c.-70-6941A>G		intron_variant		1
ESR1	ENST00000473497.5	n.205-6941A>G		intron_variant, non_coding_transcript_variant		1
ESR1	ENST00000440973.5	c.-70-6941A>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52859 AN: 151818 Hom.: 12064 Cov.: 31

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.349 AC: 52970 AN: 151936 Hom.: 12104 Cov.: 31 AF XY: 0.350 AC XY: 25963 AN XY: 74244

Gnomad4 AFR AF: 0.640

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.319

Alfa AF: 0.329 Hom.: 1635

Bravo AF: 0.373

Asia WGS AF: 0.406 AC: 1409 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.5
Dann	Benign	0.72

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: rs9478244; hg19: chr6-152122037;