Variant X-104250461-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_153448.4(ESX1):c.988G>C(p.Val330Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.000036 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

ESX1
NM_153448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.59

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08334744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESX1	NM_153448.4 linkuse as main transcript	c.988G>C	p.Val330Leu	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.988G>C	p.Val330Leu	missense_variant	4/4	1	NM_153448.4	ENSP00000361669	P1

Frequencies

GnomAD3 genomes

AF:

0.0000500

AC:

AN:

100088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

26060

show subpopulations

Gnomad AFR

AF:

0.0000361

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000112

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:

0.0000608

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000363

AC:

AN:

826493

Hom.:

Cov.:

AF XY:

0.00000799

AC XY:

AN XY:

250303

show subpopulations

Gnomad4 AFR exome

AF:

0.0000587

Gnomad4 AMR exome

AF:

0.00176

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000113

Gnomad4 SAS exome

AF:

0.0000636

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.0000608

GnomAD4 genome

AF:

0.0000499

AC:

AN:

100106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

26092

show subpopulations

Gnomad4 AFR

AF:

0.0000360

Gnomad4 AMR

AF:

0.000111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000608

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000759

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

Apr 01, 2024

The c.988G>C (p.V330L) 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 988, causing the valine (V) at amino acid position 330 to be replaced by a leucine (L). 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

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.15

DANN

Benign

0.49

DEOGEN2

Benign

0.059

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.50

M_CAP

Benign

0.018

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.040

REVEL

Benign

0.12

Sift

Benign

0.27

Sift4G

Benign

0.65

Polyphen

0.0010

Vest4

0.043

MutPred

0.29

Loss of methylation at R329 (P = 0.0952);

MVP

0.29

MPC

0.40

ClinPred

0.048

GERP RS

-1.1

Varity_R

0.052

gMVP

0.081

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