rs9397459

Variant names:

• chr6-151944524-G-A
• rs9397459
• NM_000125.4:c.1096+16G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-151944524-G-A
• chr6-151944524-G-C
• chr6-151944524-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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]

ESR1 Gene-Disease associations (from GenCC):

• estrogen resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1096+16G>A		intron_variant	Intron 4 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1096+16G>A		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

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

GnomAD2 exomes AF: 0.0203 AC: 5052 AN: 249412 AF XY: 0.0180

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 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

African (AFR) AF: 0.121 AC: 4042 AN: 33430

American (AMR) AF: 0.00640 AC: 286 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26124

East Asian (EAS) AF: 0.0707 AC: 2806 AN: 39682

South Asian (SAS) AF: 0.0158 AC: 1359 AN: 86198

European-Finnish (FIN) AF: 0.0278 AC: 1480 AN: 53318

Middle Eastern (MID) AF: 0.00840 AC: 48 AN: 5712

European-Non Finnish (NFE) AF: 0.000933 AC: 1035 AN: 1109108

Other (OTH) AF: 0.0145 AC: 877 AN: 60276

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

African (AFR) AF: 0.117 AC: 4846 AN: 41546

American (AMR) AF: 0.0127 AC: 195 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.0763 AC: 395 AN: 5178

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4830

European-Finnish (FIN) AF: 0.0269 AC: 285 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 68026

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0153 Hom.: 202

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

Jun 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9397459; hg19: chr6-152265659;