Genetic Variant NM_153448.4:c.869G>C (chrX-104250580-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_153448.4(ESX1):c.869G>C(p.Arg290Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000625 in 1,151,565 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 2 hem., cov: 21)

Exomes 𝑓: 0.000058 ( 0 hom. 22 hem. )

Consequence

ESX1
NM_153448.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007947892).

BP6

Variant X-104250580-C-G is Benign according to our data. Variant chrX-104250580-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2661112.

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.

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>C	p.Arg290Pro	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>C	p.Arg290Pro	missense	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes

AF:

0.000121

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:

0.00292

Gnomad SAS

AF:

0.000524

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000149

AC:

AN:

147967

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00151

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000152

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1060799

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

340083

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25633

American (AMR)

AF:

0.0000310

AC:

AN:

32272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17006

East Asian (EAS)

AF:

0.00105

AC:

AN:

29543

South Asian (SAS)

AF:

0.000146

AC:

AN:

47911

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39071

Middle Eastern (MID)

AF:

0.000263

AC:

AN:

3800

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

821142

Other (OTH)

AF:

0.0000900

AC:

AN:

44421

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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

AF:

0.000121

AC:

AN:

90766

Hom.:

Cov.:

AF XY:

0.0000819

AC XY:

AN XY:

24406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23581

American (AMR)

AF:

0.000116

AC:

AN:

8626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2309

East Asian (EAS)

AF:

0.00293

AC:

AN:

2735

South Asian (SAS)

AF:

0.000526

AC:

AN:

1900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

101

European-Non Finnish (NFE)

AF:

0.0000221

AC:

AN:

45212

Other (OTH)

AF:

0.00

AC:

AN:

1223

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

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:

0.00

Hom.:

ExAC

AF:

0.000108

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.4

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.56

M_CAP

Benign

0.0014

MetaRNN

Benign

0.0079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.66

PhyloP100

0.012

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

REVEL

Benign

0.048

Sift

Benign

0.046

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.022

MutPred

0.29

Gain of glycosylation at R290 (P = 0.0151)

MVP

0.082

MPC

0.59

ClinPred

0.0069

GERP RS

-5.5

Varity_R

0.18

gMVP

0.14

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over