Genetic Variant ESX1:p.Arg329Pro (chrX-104250463-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_153448.4(ESX1):c.986G>C(p.Arg329Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 810,588 control chromosomes in the GnomAD database, including 1 homozygotes. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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. R329H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., 3 hem., cov: 15)

Exomes 𝑓: 0.00011 ( 1 hom. 9 hem. )

Failed GnomAD Quality Control

Consequence

ESX1
NM_153448.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.40

Publications

4 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013727993).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

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.986G>C	p.Arg329Pro	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.986G>C	p.Arg329Pro	missense	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

154

AN:

65714

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00332

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00836

Gnomad ASJ

AF:

0.000562

Gnomad EAS

AF:

0.000460

Gnomad SAS

AF:

0.00430

Gnomad FIN

AF:

0.000368

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.00495

GnomAD2 exomes

AF:

0.000243

AC:

AN:

8217

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000364

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

AN:

810588

Hom.:

Cov.:

AF XY:

0.0000369

AC XY:

AN XY:

244028

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

16713

American (AMR)

AF:

0.00219

AC:

AN:

4557

Ashkenazi Jewish (ASJ)

AF:

0.000108

AC:

AN:

9281

East Asian (EAS)

AF:

0.000467

AC:

AN:

17126

South Asian (SAS)

AF:

0.000133

AC:

AN:

15049

European-Finnish (FIN)

AF:

0.000122

AC:

AN:

24551

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1995

European-Non Finnish (NFE)

AF:

0.0000841

AC:

AN:

689286

Other (OTH)

AF:

0.000125

AC:

AN:

32030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00236

AC:

155

AN:

65710

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

AN XY:

15584

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00331

AC:

AN:

16299

American (AMR)

AF:

0.00855

AC:

AN:

5500

Ashkenazi Jewish (ASJ)

AF:

0.000562

AC:

AN:

1780

East Asian (EAS)

AF:

0.000462

AC:

AN:

2166

South Asian (SAS)

AF:

0.00435

AC:

AN:

1379

European-Finnish (FIN)

AF:

0.000368

AC:

AN:

2716

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

34561

Other (OTH)

AF:

0.00491

AC:

AN:

815

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.311

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000197

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.70

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.088

FATHMM_MKL

Benign

0.00055

LIST_S2

Benign

0.70

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.4

PhyloP100

-4.4

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.32

REVEL

Benign

0.095

Sift

Benign

0.25

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.061

MVP

0.13

MPC

0.59

ClinPred

0.032

GERP RS

-2.5

Varity_R

0.090

gMVP

0.083

Mutation Taster

=93/7

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over