Genetic Variant ESX1:p.Arg290His (chrX-104250580-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153448.4(ESX1):c.869G>A(p.Arg290His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000174 in 1,151,523 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R290P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000011 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 9.4e-7 ( 0 hom. 1 hem. )

Consequence

ESX1
NM_153448.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0120

Publications

3 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045601815).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESX1	NM_153448.4	MANE Select	c.869G>A	p.Arg290His	missense	Exon 4 of 4	NP_703149.1	Q8N693

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESX1	ENST00000372588.4	TSL:1 MANE Select	c.869G>A	p.Arg290His	missense	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes

AF:

0.0000110

AC:

AN:

90724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000116

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.43e-7

AC:

AN:

1060799

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

340083

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25633

American (AMR)

AF:

0.00

AC:

AN:

32272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17006

East Asian (EAS)

AF:

0.00

AC:

AN:

29543

South Asian (SAS)

AF:

0.0000209

AC:

AN:

47911

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39071

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3800

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

821143

Other (OTH)

AF:

0.00

AC:

AN:

44420

GnomAD4 genome

AF:

0.0000110

AC:

AN:

90724

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

24370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23533

American (AMR)

AF:

0.000116

AC:

AN:

8617

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2309

East Asian (EAS)

AF:

0.00

AC:

AN:

2742

South Asian (SAS)

AF:

0.00

AC:

AN:

1908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

106

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

45220

Other (OTH)

AF:

0.00

AC:

AN:

1210

Age Distribution

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.0

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.086

FATHMM_MKL

Benign

0.0088

LIST_S2

Benign

0.67

M_CAP

Benign

0.0039

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.012

PrimateAI

Benign

0.47

PROVEAN

Benign

2.1

REVEL

Benign

0.14

Sift

Benign

0.18

Sift4G

Benign

0.58

Polyphen

0.031

Vest4

0.094

MutPred

0.33

Loss of methylation at R290 (P = 0.033)

MVP

0.27

MPC

0.50

ClinPred

0.059

GERP RS

-5.5

Varity_R

0.024

gMVP

0.10

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over