Genetic Variant ESR1:p.Pro146Leu (chr6-151808349-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000125.4(ESR1):c.437C>T(p.Pro146Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000294 in 1,362,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P146Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ESR1
NM_000125.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.90

Publications

13 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

ESR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.418346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.437C>T	p.Pro146Leu	missense_variant	Exon 1 of 8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 link	c.437C>T	p.Pro146Leu	missense_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000730

AC:

AN:

137080

AF XY:

0.0000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000294

AC:

AN:

1362382

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

668850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30424

American (AMR)

AF:

0.00

AC:

AN:

33166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21940

East Asian (EAS)

AF:

0.00

AC:

AN:

35832

South Asian (SAS)

AF:

0.00

AC:

AN:

73846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4022

European-Non Finnish (NFE)

AF:

0.00000375

AC:

AN:

1067028

Other (OTH)

AF:

0.00

AC:

AN:

56020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000889

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

T;T;T;T;T;T

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.076

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

.;.;D;.;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.42

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L;L;L;.;.

PhyloP100

5.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.7

N;N;N;N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.024

D;D;D;D;D;D

Sift4G

Benign

0.078

T;T;T;T;D;T

Polyphen

0.013

B;B;B;B;D;.

Vest4

0.34

MutPred

0.68

Gain of MoRF binding (P = 0.0737);Gain of MoRF binding (P = 0.0737);Gain of MoRF binding (P = 0.0737);Gain of MoRF binding (P = 0.0737);Gain of MoRF binding (P = 0.0737);Gain of MoRF binding (P = 0.0737);

MVP

0.48

MPC

0.53

ClinPred

0.67

GERP RS

4.9

Varity_R

0.15

gMVP

0.41

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over