Variant X-104250506-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_153448.4(ESX1):c.943G>T(p.Gly315Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 1 hem., cov: 20)

Exomes 𝑓: 0.000018 ( 0 hom. 12 hem. )

Failed GnomAD Quality Control

Consequence

ESX1
NM_153448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.384

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 -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30838984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESX1	NM_153448.4 linkuse as main transcript	c.943G>T	p.Gly315Trp	missense_variant	4/4	ENST00000372588.4	NP_703149.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESX1	ENST00000372588.4 linkuse as main transcript	c.943G>T	p.Gly315Trp	missense_variant	4/4	1	NM_153448.4	ENSP00000361669	P1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

101402

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

27782

show subpopulations

Gnomad AFR

AF:

0.0000352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000548

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000341

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000204

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000122

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000175

AC:

AN:

912107

Hom.:

Cov.:

AF XY:

0.0000430

AC XY:

AN XY:

279263

show subpopulations

Gnomad4 AFR exome

AF:

0.000103

Gnomad4 AMR exome

AF:

0.0000934

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000380

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000160

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000148

AC:

AN:

101440

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

27828

show subpopulations

Gnomad4 AFR

AF:

0.0000351

Gnomad4 AMR

AF:

0.000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000342

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000204

Gnomad4 NFE

AF:

0.000122

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.943G>T (p.G315W) alteration is located in exon 4 (coding exon 4) of the ESX1 gene. This alteration results from a G to T substitution at nucleotide position 943, causing the glycine (G) at amino acid position 315 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.39

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Sift4G

Benign

0.095

Polyphen

1.0

Vest4

0.30

MutPred

0.38

Loss of catalytic residue at P311 (P = 0.0746);

MVP

0.55

MPC

0.48

ClinPred

0.40

GERP RS

2.0

Varity_R

0.032

gMVP

0.069

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