chr6-151807928-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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). Synonymous variant affecting the same amino acid position (i.e. H6H) has been classified as Likely benign.

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 was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.00327

AC:

811

AN:

248082

AF XY:

0.00323

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 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

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.000872

AC:

AN:

44718

Gnomad4 ASJ exome

AF:

0.00390

AC:

102

AN:

26130

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39690

Gnomad4 SAS exome

AF:

0.00134

AC:

116

AN:

86246

Gnomad4 FIN exome

AF:

0.00443

AC:

236

AN:

53252

Gnomad4 NFE exome

AF:

0.00534

AC:

5942

AN:

1111900

Gnomad4 Remaining exome

AF:

0.00543

AC:

328

AN:

60386

Heterozygous variant carriers

355

710

1064

1419

1774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.00308

AC:

469

AN:

152316

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000722

AC:

0.000721501

AN:

0.000721501

Gnomad4 AMR

AF:

0.00157

AC:

0.00156822

AN:

0.00156822

Gnomad4 ASJ

AF:

0.00346

AC:

0.00345622

AN:

0.00345622

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00166

AC:

0.001657

AN:

0.001657

Gnomad4 FIN

AF:

0.00348

AC:

0.00348268

AN:

0.00348268

Gnomad4 NFE

AF:

0.00517

AC:

0.00517434

AN:

0.00517434

Gnomad4 OTH

AF:

0.00284

AC:

0.00284091

AN:

0.00284091

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00437

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

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ESR1: PP3, BS2 -

Dec 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ESR1-related disorder

Benign:1

Jun 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Mutation Taster

=94/6

polymorphism

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