chr6-151807928-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000125.4(ESR1):c.16C>T(p.His6Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0045 in 1,613,882 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 23 hom. )

Consequence

ESR1
NM_000125.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.94

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012596518).

BP6

Variant 6-151807928-C-T is Benign according to our data. Variant chr6-151807928-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 712708.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS2

High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.16C>T	p.His6Tyr	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.16C>T	p.His6Tyr	missense_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

470

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00519

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00327

AC:

811

AN:

248082

Hom.:

AF XY:

0.00323

AC XY:

435

AN XY:

134520

show subpopulations

Gnomad AFR exome

AF:

0.000746

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00431

Gnomad NFE exome

AF:

0.00515

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00465

AC:

6791

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

3266

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00134

Gnomad4 FIN exome

AF:

0.00443

Gnomad4 NFE exome

AF:

0.00534

Gnomad4 OTH exome

AF:

0.00543

GnomAD4 genome

AF:

0.00308

AC:

469

AN:

152316

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00348

Gnomad4 NFE

AF:

0.00517

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00431

Hom.:

Bravo

AF:

0.00273

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00348

AC:

422

EpiCase

AF:

0.00529

EpiControl

AF:

0.00534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ESR1: PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2024	Identified in an individual with primary ovarian insufficiency, however, functional studies in HEK293T cells demonstrated that the variant showed similar transcriptional activity to wild type (PMID: 27603904); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23074960, 27603904, 34662886, 36099812) -

ESR1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;T;T;T;T;T;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.97

D;.;.;D;D;.;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.013

T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

0.63

.;N;N;.;N;N;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

D;N;N;D;N;N;N;N

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

D;D;D;T;D;D;D;D

Sift4G

Pathogenic

0.0

D;T;T;D;T;T;D;D

Polyphen

0.99, 1.0

.;D;D;.;D;D;D;.

Vest4

0.56, 0.56, 0.55, 0.52, 0.30, 0.40

MVP

0.80

MPC

1.3

ClinPred

0.047

GERP RS

5.2

Varity_R

0.16

gMVP

0.74

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over