Genetic Variant ESX1:p.Trp297Gly (chrX-104250560-A-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_153448.4(ESX1):c.889T>G(p.Trp297Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,121,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 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 (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.00012 ( 0 hom. 41 hem. )

Consequence

ESX1
NM_153448.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.58

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01248306).

BP6

Variant X-104250560-A-C is Benign according to our data. Variant chrX-104250560-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2673250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 4 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.889T>G	p.Trp297Gly	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.889T>G	p.Trp297Gly	missense	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes

AF:

0.000239

AC:

AN:

96250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000216

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:

0.000233

Gnomad OTH

AF:

0.000752

GnomAD2 exomes

AF:

0.000108

AC:

AN:

119915

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.000513

Gnomad AMR exome

AF:

0.0000571

Gnomad ASJ exome

AF:

0.000338

Gnomad EAS exome

AF:

0.0000947

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000905

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

122

AN:

1025483

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

323447

show subpopulations

African (AFR)

AF:

0.000542

AC:

AN:

23978

American (AMR)

AF:

0.0000380

AC:

AN:

26337

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15162

East Asian (EAS)

AF:

0.0000701

AC:

AN:

28541

South Asian (SAS)

AF:

0.0000471

AC:

AN:

42454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37643

Middle Eastern (MID)

AF:

0.000288

AC:

AN:

3475

European-Non Finnish (NFE)

AF:

0.000116

AC:

AN:

805114

Other (OTH)

AF:

0.000234

AC:

AN:

42779

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000239

AC:

AN:

96279

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

26199

show subpopulations

African (AFR)

AF:

0.000355

AC:

AN:

25358

American (AMR)

AF:

0.000215

AC:

AN:

9288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2447

East Asian (EAS)

AF:

0.00

AC:

AN:

2955

South Asian (SAS)

AF:

0.00

AC:

AN:

2164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4755

Middle Eastern (MID)

AF:

0.00

AC:

AN:

126

European-Non Finnish (NFE)

AF:

0.000233

AC:

AN:

47272

Other (OTH)

AF:

0.000743

AC:

AN:

1345

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000873

Hom.:

ExAC

AF:

0.000102

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

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

0.050

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.042

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.050

FATHMM_MKL

Benign

0.00071

LIST_S2

Benign

0.33

M_CAP

Benign

0.013

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.9

PhyloP100

-2.6

PrimateAI

Benign

0.48

PROVEAN

Benign

0.40

REVEL

Benign

0.034

Sift

Benign

1.0

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.13

MVP

0.14

MPC

0.72

ClinPred

0.0088

GERP RS

-5.2

Varity_R

0.056

gMVP

0.18

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over