rs9397459

chr6-151944524-G-Achr6-151944524-G-Cchr6-151944524-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000125.4(ESR1):c.1096+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,610,848 control chromosomes in the GnomAD database, including 710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (292 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (418 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.848

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-151944524-G-A is Benign according to our data. Variant chr6-151944524-G-A is described in ClinVar as [Benign]. Clinvar id is 1239923.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.1096+16G>A		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.1096+16G>A		intron_variant		1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6025 AN: 152162 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0757

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0203 AC: 5052 AN: 249412 Hom.: 184 AF XY: 0.0180 AC XY: 2432 AN XY: 134900

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.00532

Gnomad ASJ exome AF: 0.00508

Gnomad EAS exome AF: 0.0801

Gnomad SAS exome AF: 0.0158

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00825 AC: 12027 AN: 1458568 Hom.: 418 Cov.: 33 AF XY: 0.00816 AC XY: 5922 AN XY: 725816

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.00640

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.0707

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.000933

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0396 AC: 6033 AN: 152280 Hom.: 292 Cov.: 32 AF XY: 0.0402 AC XY: 2995 AN XY: 74470

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0763

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0113 Hom.: 103

Bravo AF: 0.0419

Asia WGS AF: 0.0460 AC: 161 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	6.5
Dann	Benign	0.83

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: rs9397459; hg19: chr6-152265659;