chr6-151808202-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000125.4(ESR1):c.290T>C(p.Phe97Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,571,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

ESR1
NM_000125.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4027321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.290T>C	p.Phe97Ser	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.290T>C	p.Phe97Ser	missense_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000916

AC:

AN:

1419548

Hom.:

Cov.:

AF XY:

0.00000712

AC XY:

AN XY:

701822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32606

American (AMR)

AF:

0.00

AC:

AN:

38776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

37626

South Asian (SAS)

AF:

0.00

AC:

AN:

81238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

1090830

Other (OTH)

AF:

0.00

AC:

AN:

58724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41324

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67932

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.290T>C (p.F97S) alteration is located in exon 1 (coding exon 1) of the ESR1 gene. This alteration results from a T to C substitution at nucleotide position 290, causing the phenylalanine (F) at amino acid position 97 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

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

Eigen

Benign

0.055

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.084

MetaRNN

Benign

0.40

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M;.;M;M;.;.

PhyloP100

2.5

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.29

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

REVEL

Benign

0.10

Sift

Benign

0.30

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

Sift4G

Benign

0.30

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

Polyphen

0.30

B;B;.;B;B;D;.

Vest4

0.58

MutPred

0.58

Gain of glycosylation at F97 (P = 0.0046);Gain of glycosylation at F97 (P = 0.0046);Gain of glycosylation at F97 (P = 0.0046);Gain of glycosylation at F97 (P = 0.0046);Gain of glycosylation at F97 (P = 0.0046);Gain of glycosylation at F97 (P = 0.0046);Gain of glycosylation at F97 (P = 0.0046);

MVP

0.60

MPC

1.2

ClinPred

0.69

GERP RS

3.8

Varity_R

0.15

gMVP

0.58

Mutation Taster

=90/10

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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chr6-151808202-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over