rs9340773

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000125.4(ESR1):c.229G>A(p.Gly77Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,604,744 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0013 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 83 hom. )

Consequence

ESR1
NM_000125.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.48

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:

ESR1 (HGNC:):

ESR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039296746).

BP6

Variant 6-151808141-G-A is Benign according to our data. Variant chr6-151808141-G-A is described in ClinVar as [Benign]. Clinvar id is 790835.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00125 (191/152284) while in subpopulation SAS AF= 0.0389 (188/4830). AF 95% confidence interval is 0.0344. There are 7 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_000125.4 linkuse as main transcript	c.229G>A	p.Gly77Ser	missense_variant	1/8	ENST00000206249.8	NP_000116.2	P03372-1G4XH65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 linkuse as main transcript	c.229G>A	p.Gly77Ser	missense_variant	1/8	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

188

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0383

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00456

AC:

1014

AN:

222528

Hom.:

AF XY:

0.00603

AC XY:

734

AN XY:

121730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0349

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.00253

GnomAD4 exome

AF:

0.00201

AC:

2914

AN:

1452460

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

2065

AN XY:

721658

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000687

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000509

Gnomad4 SAS exome

AF:

0.0322

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000217

Gnomad4 OTH exome

AF:

0.00252

GnomAD4 genome

AF:

0.00125

AC:

191

AN:

152284

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0389

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000189

ExAC

AF:

0.00507

AC:

611

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

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

0.067

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.23

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

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.85

T;.;.;D;D;.;D;D

MetaRNN

Benign

0.0039

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.57

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

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.17

N;N;N;N;N;N;N;N

REVEL

Benign

0.065

Sift

Benign

0.61

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

Sift4G

Benign

0.99

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

Polyphen

0.0020, 0.98

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

Vest4

0.050, 0.046, 0.040, 0.043, 0.064

MutPred

0.32

Gain of glycosylation at G77 (P = 0.0056);Gain of glycosylation at G77 (P = 0.0056);Gain of glycosylation at G77 (P = 0.0056);Gain of glycosylation at G77 (P = 0.0056);Gain of glycosylation at G77 (P = 0.0056);Gain of glycosylation at G77 (P = 0.0056);Gain of glycosylation at G77 (P = 0.0056);Gain of glycosylation at G77 (P = 0.0056);

MVP

0.56

MPC

0.53

ClinPred

0.11

GERP RS

2.4

Varity_R

0.055

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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