rs2228480

chr6-152098960-G-Achr6-152098960-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000125.4(ESR1):c.1782G>A(p.Thr594=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,612,120 control chromosomes in the GnomAD database, including 29,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2469 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26882 hom.)
• Consequence: ESR1 NM_000125.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.344

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-152098960-G-A is Benign according to our data. Variant chr6-152098960-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1263746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.344 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.1782G>A	p.Thr594=	synonymous_variant	8/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.1782G>A	p.Thr594=	synonymous_variant	8/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27192 AN: 152006 Hom.: 2462 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.194 AC: 48493 AN: 250380 Hom.: 4939 AF XY: 0.190 AC XY: 25680 AN XY: 135304

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.219

Gnomad SAS exome AF: 0.193

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.190 AC: 276902 AN: 1459992 Hom.: 26882 Cov.: 31 AF XY: 0.189 AC XY: 136931 AN XY: 726374

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.265

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.179 AC: 27235 AN: 152128 Hom.: 2469 Cov.: 32 AF XY: 0.181 AC XY: 13439 AN XY: 74386

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.162

Alfa AF: 0.176 Hom.: 4394

Bravo AF: 0.182

Asia WGS AF: 0.212 AC: 737 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.169

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2018

This variant is associated with the following publications: (PMID: 15934440, 19636371, 19860576) -

ESR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cancer of breast;C1832662:Myocardial infarction, susceptibility to;C3809250:Estrogen resistance syndrome;C3887485:Migraine with or without aura, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

Migraine with or without aura, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.093
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2228480; hg19: chr6-152420095; COSMIC: COSV52780915; COSMIC: COSV52780915;