NM_000125.4:c.644-1859G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000125.4(ESR1):​c.644-1859G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 151,954 control chromosomes in the GnomAD database, including 7,644 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 0.32 ( 7644 hom., cov: 32)

Consequence

ESR1
NM_000125.4 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.288

Publications

18 publications found
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]
ESR1 Gene-Disease associations (from GenCC):
  • estrogen resistance syndrome
    Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ESR1NM_000125.4 linkc.644-1859G>A intron_variant Intron 2 of 7 ENST00000206249.8 NP_000116.2 P03372-1G4XH65

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ESR1ENST00000206249.8 linkc.644-1859G>A intron_variant Intron 2 of 7 1 NM_000125.4 ENSP00000206249.3 P03372-1

Frequencies

GnomAD3 genomes
AF:
0.317
AC:
48185
AN:
151836
Hom.:
7645
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.310
Gnomad AMI
AF:
0.330
Gnomad AMR
AF:
0.298
Gnomad ASJ
AF:
0.343
Gnomad EAS
AF:
0.206
Gnomad SAS
AF:
0.233
Gnomad FIN
AF:
0.268
Gnomad MID
AF:
0.364
Gnomad NFE
AF:
0.347
Gnomad OTH
AF:
0.320
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.317
AC:
48204
AN:
151954
Hom.:
7644
Cov.:
32
AF XY:
0.309
AC XY:
22945
AN XY:
74264
show subpopulations
African (AFR)
AF:
0.310
AC:
12813
AN:
41390
American (AMR)
AF:
0.298
AC:
4546
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.343
AC:
1190
AN:
3472
East Asian (EAS)
AF:
0.206
AC:
1064
AN:
5172
South Asian (SAS)
AF:
0.232
AC:
1117
AN:
4812
European-Finnish (FIN)
AF:
0.268
AC:
2829
AN:
10548
Middle Eastern (MID)
AF:
0.354
AC:
104
AN:
294
European-Non Finnish (NFE)
AF:
0.347
AC:
23567
AN:
67974
Other (OTH)
AF:
0.319
AC:
673
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1738
3476
5213
6951
8689
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
484
968
1452
1936
2420
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.333
Hom.:
8987
Bravo
AF:
0.320
Asia WGS
AF:
0.240
AC:
836
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
CADD
Benign
0.81
DANN
Benign
0.17
PhyloP100
-0.29
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

Publications

Other links and lift over

dbSNP: rs9340835; hg19: chr6-152199931; COSMIC: COSV52785408; COSMIC: COSV52785408; API