6-151808349-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000125.4(ESR1):c.437C>A(p.Pro146Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00186 in 1,511,840 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0030 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 46 hom. )

Consequence

ESR1
NM_000125.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.90

Publications

13 publications found

Variant links:

COSMIC-nc: COSV105858278

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004661292).

BP6

Variant 6-151808349-C-A is Benign according to our data. Variant chr6-151808349-C-A is described in ClinVar as Benign. ClinVar VariationId is 3341627.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00296 (443/149476) while in subpopulation EAS AF = 0.0278 (137/4922). AF 95% confidence interval is 0.024. There are 6 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.437C>A	p.Pro146Gln	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>A	p.Pro146Gln	missense_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

445

AN:

149400

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0175

Gnomad ASJ

AF:

0.000868

Gnomad EAS

AF:

0.0281

Gnomad SAS

AF:

0.00232

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00387

GnomAD2 exomes

AF:

0.00585

AC:

802

AN:

137080

AF XY:

0.00516

show subpopulations

Gnomad AFR exome

AF:

0.000361

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0250

Gnomad FIN exome

AF:

0.000114

Gnomad NFE exome

AF:

0.000216

Gnomad OTH exome

AF:

0.00552

GnomAD4 exome

AF:

0.00174

AC:

2369

AN:

1362364

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1173

AN XY:

668842

show subpopulations

African (AFR)

AF:

0.000296

AC:

AN:

30424

American (AMR)

AF:

0.0187

AC:

620

AN:

33158

Ashkenazi Jewish (ASJ)

AF:

0.000273

AC:

AN:

21940

East Asian (EAS)

AF:

0.0401

AC:

1435

AN:

35828

South Asian (SAS)

AF:

0.00177

AC:

131

AN:

73842

European-Finnish (FIN)

AF:

0.0000499

AC:

AN:

40102

Middle Eastern (MID)

AF:

0.000249

AC:

AN:

4022

European-Non Finnish (NFE)

AF:

0.0000544

AC:

AN:

1067028

Other (OTH)

AF:

0.00191

AC:

107

AN:

56020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

129

258

388

517

646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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

AF:

0.00296

AC:

443

AN:

149476

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

257

AN XY:

73058

show subpopulations

African (AFR)

AF:

0.000424

AC:

AN:

40052

American (AMR)

AF:

0.0175

AC:

260

AN:

14846

Ashkenazi Jewish (ASJ)

AF:

0.000868

AC:

AN:

3458

East Asian (EAS)

AF:

0.0278

AC:

137

AN:

4922

South Asian (SAS)

AF:

0.00232

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67754

Other (OTH)

AF:

0.00385

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00357

ExAC

AF:

0.00351

AC:

395

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ESR1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T;T;T;T;T

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.69

.;.;T;.;T;T

MetaRNN

Benign

0.0047

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.0

M;M;M;M;.;.

PhyloP100

5.9

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.71

N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.11

T;T;T;T;D;D

Sift4G

Benign

0.20

T;T;T;T;D;D

Polyphen

0.93

P;P;P;P;D;.

Vest4

0.30

MVP

0.53

MPC

1.1

ClinPred

0.044

GERP RS

4.9

Varity_R

0.14

gMVP

0.37

Mutation Taster

=89/11

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over