rs9340978

Positions:

• chr6-152012810-G-A

Variant summary

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

The NM_000125.4(ESR1):​c.1235+1016G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 152,210 control chromosomes in the GnomAD database, including 224 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 0.049 (224 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0590

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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1235+1016G>A		intron_variant		ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1235+1016G>A		intron_variant		1	NM_000125.4	ENSP00000206249	P1

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7399 AN: 152092 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0636

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

GnomAD4 genome AF: 0.0486 AC: 7399 AN: 152210 Hom.: 224 Cov.: 32 AF XY: 0.0477 AC XY: 3548 AN XY: 74396

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.0523

Gnomad4 ASJ AF: 0.0861

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.0464

Gnomad4 NFE AF: 0.0653

Gnomad4 OTH AF: 0.0630

Alfa AF: 0.0645 Hom.: 495

Bravo AF: 0.0483

Asia WGS AF: 0.0140 AC: 48 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.71

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: rs9340978; hg19: chr6-152333945; COSMIC: COSV52800858;