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rs2228480

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.344
Variant links:
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]

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ACMG classification

Classification made for transcript

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
ESR1NM_000125.4 linkuse as main transcriptc.1782G>A p.Thr594= synonymous_variant 8/8 ENST00000206249.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ESR1ENST00000206249.8 linkuse as main transcriptc.1782G>A p.Thr594= synonymous_variant 8/81 NM_000125.4 P1P03372-1

Frequencies

GnomAD3 genomes
AF:
0.179
AC:
27192
AN:
152006
Hom.:
2462
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

ESR1-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 11, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxAug 17, 2018This variant is associated with the following publications: (PMID: 15934440, 19636371, 19860576) -
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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 23, 2022- -
Migraine with or without aura, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2228480; hg19: chr6-152420095; COSMIC: COSV52780915; COSMIC: COSV52780915; API