6-151808318-C-T

Position:

chr6-151808318-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_000125.4(ESR1):c.406C>T(p.Pro136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,558,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ESR1
NM_000125.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 2.50

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0039950907).

BP6

Variant 6-151808318-C-T is Benign according to our data. Variant chr6-151808318-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 709059.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_000125.4 linkuse as main transcript	c.406C>T	p.Pro136Ser	missense_variant	1/8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 linkuse as main transcript	c.406C>T	p.Pro136Ser	missense_variant	1/8	1	NM_000125.4	ENSP00000206249	P1	P03372-1

Frequencies

GnomAD3 genomes

AF:

0.000961

AC:

146

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000243

AC:

AN:

177238

Hom.:

AF XY:

0.000205

AC XY:

AN XY:

97336

show subpopulations

Gnomad AFR exome

AF:

0.00386

Gnomad AMR exome

AF:

0.0000359

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000134

AC:

189

AN:

1406734

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

694418

show subpopulations

Gnomad4 AFR exome

AF:

0.00508

Gnomad4 AMR exome

AF:

0.000103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000276

Gnomad4 OTH exome

AF:

0.000259

GnomAD4 genome

AF:

0.000960

AC:

146

AN:

152100

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000685

Hom.:

Bravo

AF:

0.00108

ESP6500AA

AF:

0.00213

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000213

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ESR1 p.Pro136Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs201145204) and in control databases in 72 of 208534 chromosomes at a frequency of 0.000345 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 71 of 19540 chromosomes (freq: 0.003634) and Latino in 1 of 28696 chromosomes (freq: 0.000035), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other or South Asian populations. The p.Pro136 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.25

T;T;T;T;T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.84

.;.;T;.;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.0040

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;N;N;N;.;.

MutationTaster

Benign

0.73

N;N;N;N;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.010

N;N;N;N;N;N

REVEL

Benign

0.027

Sift

Benign

0.36

T;T;T;T;D;T

Sift4G

Benign

0.55

T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;.

Vest4

0.20

MVP

0.40

MPC

0.52

ClinPred

0.093

GERP RS

4.1

Varity_R

0.11

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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