X-104250580-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -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. 14/20 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

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 made for transcript

Verdict is Likely_benign. Variant got -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 id is 2661112.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESX1	NM_153448.4 link	c.869G>C	p.Arg290Pro	missense_variant	Exon 4 of 4	ENST00000372588.4	NP_703149.1	Q8N693

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESX1	ENST00000372588.4 link	c.869G>C	p.Arg290Pro	missense_variant	Exon 4 of 4	1	NM_153448.4	ENSP00000361669.4		Q8N693

Frequencies

GnomAD3 genomes

AF:

0.000121

AC:

AN:

90724

Hom.:

Cov.:

AF XY:

0.0000821

AC XY:

AN XY:

24370

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

GnomAD3 exomes

AF:

0.000149

AC:

AN:

147967

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

45189

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 SAS exome

AF:

0.000164

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000310

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00105

Gnomad4 SAS exome

AF:

0.000146

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000900

GnomAD4 genome

AF:

0.000121

AC:

AN:

90766

Hom.:

Cov.:

AF XY:

0.0000819

AC XY:

AN XY:

24406

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000116

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00293

Gnomad4 SAS

AF:

0.000526

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000221

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.869G>C (p.R290P) alteration is located in exon 4 (coding exon 4) of the ESX1 gene. This alteration results from a G to C substitution at nucleotide position 869, causing the arginine (R) at amino acid position 290 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ESX1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.4

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over