Genetic Variant ESX1:p.Arg290Leu (chrX-104250580-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153448.4(ESX1):c.869G>T(p.Arg290Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000943 in 1,060,801 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 0.0 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045746565).

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>T	p.Arg290Leu	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>T	p.Arg290Leu	missense	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

90724

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000676

AC:

AN:

147967

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000873

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

9.43e-7

AC:

AN:

1060801

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

340085

show subpopulations

African (AFR)

AF:

0.0000390

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:

0.00

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:

821144

Other (OTH)

AF:

0.00

AC:

AN:

44421

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

90724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

24370

African (AFR)

AF:

0.00

AC:

AN:

23533

American (AMR)

AF:

0.00

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.15

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.063

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.61

M_CAP

Benign

0.0041

MetaRNN

Benign

0.046

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

PhyloP100

0.012

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.25

REVEL

Benign

0.10

Sift

Benign

0.20

Sift4G

Benign

0.74

Polyphen

0.0020

Vest4

0.082

MutPred

0.40

Loss of methylation at R290 (P = 0.033)

MVP

0.14

MPC

0.50

ClinPred

0.011

GERP RS

-5.5

Varity_R

0.048

gMVP

0.19

Mutation Taster

=99/1

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