Genetic Variant ESX1:p.Pro289Ser (chrX-104250584-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_ModerateBP6_ModerateBS2_Supporting

The NM_153448.4(ESX1):c.865C>T(p.Pro289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000433 in 1,178,044 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P289P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000043 ( 0 hom. 18 hem. )

Consequence

ESX1
NM_153448.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0220

Variant links:

Genes affected

ESX1 (HGNC:14865): (ESX homeobox 1) This gene encodes a dual-function 65 kDa protein that undergoes proteolytic cleavage to produce a 45 kDa N-terminal fragment with a paired-like homeodomain and a 20 kDa C-terminal fragment with a proline-rich domain. The C-terminal fragment localizes to the cytoplasm while the N-terminal fragment localizes exclusively to the nucleus. In contrast to human, the mouse homolog has a novel PN/PF motif in the C-terminus and is paternally imprinted in placental tissue. This gene likely plays a role in placental development and spermatogenesis. [provided by RefSeq, Jan 2010]

ESX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21482259).

BP6

Variant X-104250584-G-A is Benign according to our data. Variant chrX-104250584-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2661114.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 2 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESX1	NM_153448.4 link	c.865C>T	p.Pro289Ser	missense_variant	Exon 4 of 4	ENST00000372588.4	NP_703149.1	Q8N693

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESX1	ENST00000372588.4 link	c.865C>T	p.Pro289Ser	missense_variant	Exon 4 of 4	1	NM_153448.4	ENSP00000361669.4		Q8N693

Frequencies

GnomAD3 genomes

AF:

0.0000452

AC:

AN:

110643

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000291

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000573

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000525

AC:

AN:

152304

AF XY:

0.0000635

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000155

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1067360

Hom.:

Cov.:

AF XY:

0.0000522

AC XY:

AN XY:

344604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25824

American (AMR)

AF:

0.00

AC:

AN:

33005

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17386

East Asian (EAS)

AF:

0.0000673

AC:

AN:

29736

South Asian (SAS)

AF:

0.00

AC:

AN:

49185

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3850

European-Non Finnish (NFE)

AF:

0.0000534

AC:

AN:

824282

Other (OTH)

AF:

0.00

AC:

AN:

44740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000452

AC:

AN:

110684

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

33130

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30652

American (AMR)

AF:

0.00

AC:

AN:

10593

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2619

East Asian (EAS)

AF:

0.000292

AC:

AN:

3426

South Asian (SAS)

AF:

0.00

AC:

AN:

2647

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.0000573

AC:

AN:

52360

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000337

Hom.:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ESX1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.45

CADD

Benign

2.6

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.26

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.51

M_CAP

Benign

0.029

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.7

PhyloP100

0.022

PrimateAI

Benign

0.46

PROVEAN

Benign

0.26

REVEL

Benign

0.24

Sift

Uncertain

0.026

Sift4G

Benign

0.57

Polyphen

0.98

Vest4

0.15

MVP

0.52

MPC

0.41

ClinPred

0.037

GERP RS

3.2

Varity_R

0.054

gMVP

0.20

Mutation Taster

=96/4

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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chrX-104250584-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over