Genetic Variant ESX1:p.Gly288Gly (chrX-104250585-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBP6_ModerateBP7BS2_Supporting

The NM_153448.4(ESX1):c.864G>C(p.Gly288Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 110,345 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000044 ( 0 hom. 18 hem. )

Failed GnomAD Quality Control

Consequence

ESX1
NM_153448.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.248

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:

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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 (BayesDel_noAF=-0.82).

BP6

Variant X-104250585-C-G is Benign according to our data. Variant chrX-104250585-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2661115.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.248 with no splicing effect.

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.864G>C	p.Gly288Gly	synonymous	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.864G>C	p.Gly288Gly	synonymous	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes

AF:

0.0000453

AC:

AN:

110291

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000293

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000573

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000524

AC:

AN:

152531

AF XY:

0.0000635

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000155

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000440

AC:

AN:

1068515

Hom.:

Cov.:

AF XY:

0.0000522

AC XY:

AN XY:

344695

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25822

American (AMR)

AF:

0.00

AC:

AN:

33017

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17387

East Asian (EAS)

AF:

0.0000673

AC:

AN:

29703

South Asian (SAS)

AF:

0.00

AC:

AN:

49254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3850

European-Non Finnish (NFE)

AF:

0.0000545

AC:

AN:

825292

Other (OTH)

AF:

0.00

AC:

AN:

44760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

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:

0.0000453

AC:

AN:

110345

Hom.:

Cov.:

AF XY:

0.0000609

AC XY:

AN XY:

32847

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30502

American (AMR)

AF:

0.00

AC:

AN:

10543

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2621

East Asian (EAS)

AF:

0.000294

AC:

AN:

3404

South Asian (SAS)

AF:

0.00

AC:

AN:

2620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

207

European-Non Finnish (NFE)

AF:

0.0000573

AC:

AN:

52331

Other (OTH)

AF:

0.00

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000506

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.4

(source)

DANN

Benign

0.44

PhyloP100

-0.25

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