NM_000125.4:c.352T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000125.4(ESR1):c.352T>C(p.Ser118Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00449 in 1,584,834 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 25 hom. )

Consequence

ESR1
NM_000125.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.36

Publications

20 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009224892).

BP6

Variant 6-151808264-T-C is Benign according to our data. Variant chr6-151808264-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 790988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.352T>C	p.Ser118Pro	missense_variant	Exon 1 of 8	ENST00000206249.8	NP_000116.2	P03372-1G4XH65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 link	c.352T>C	p.Ser118Pro	missense_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

633

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00482

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00439

AC:

867

AN:

197410

AF XY:

0.00421

show subpopulations

Gnomad AFR exome

AF:

0.000730

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.00506

Gnomad OTH exome

AF:

0.00596

GnomAD4 exome

AF:

0.00452

AC:

6475

AN:

1432594

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3103

AN XY:

709262

show subpopulations

African (AFR)

AF:

0.000454

AC:

AN:

33062

American (AMR)

AF:

0.00383

AC:

158

AN:

41302

Ashkenazi Jewish (ASJ)

AF:

0.0000792

AC:

AN:

25242

East Asian (EAS)

AF:

0.00

AC:

AN:

38790

South Asian (SAS)

AF:

0.000438

AC:

AN:

82100

European-Finnish (FIN)

AF:

0.0164

AC:

806

AN:

49214

Middle Eastern (MID)

AF:

0.000741

AC:

AN:

5398

European-Non Finnish (NFE)

AF:

0.00476

AC:

5229

AN:

1098338

Other (OTH)

AF:

0.00380

AC:

225

AN:

59148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

363

725

1088

1450

1813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00416

AC:

633

AN:

152240

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

350

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41556

American (AMR)

AF:

0.00470

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0179

AC:

190

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00482

AC:

328

AN:

68010

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.00311

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000970

AC:

ESP6500EA

AF:

0.00331

AC:

ExAC

AF:

0.00372

AC:

444

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 09, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ESR1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;T;T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.91

.;.;D;.;D;D

MetaRNN

Benign

0.0092

T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.7

M;M;M;M;.;.

PhyloP100

4.4

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.6

D;D;D;D;N;D

REVEL

Benign

0.15

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.039

D;D;D;D;D;D

Polyphen

0.039

B;B;B;B;D;.

Vest4

0.37

MVP

0.64

MPC

1.5

ClinPred

0.035

GERP RS

4.9

Varity_R

0.72

gMVP

0.73

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_000125.4:c.352T>C

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