Variant X-104250529-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The ENST00000372588.4(ESX1):c.920C>T(p.Pro307Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000916 in 1,092,213 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000092 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000092 ( 0 hom. 4 hem. )

Consequence

ESX1
ENST00000372588.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00400

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06794274).

BS2

High Hemizygotes in GnomAdExome4 at 4 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/exons	MANE	Protein	UniProt
ESX1	NM_153448.4 linkuse as main transcript	c.920C>T	p.Pro307Leu	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.920C>T	p.Pro307Leu	missense_variant	4/4	1	NM_153448.4	ENSP00000361669	P1

Frequencies

GnomAD3 genomes

AF:

0.00000919

AC:

AN:

108781

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31581

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000299

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

82105

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

20881

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000139

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000258

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000915

AC:

AN:

983432

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

308556

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000391

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000561

Gnomad4 NFE exome

AF:

0.00000381

Gnomad4 OTH exome

AF:

0.0000490

GnomAD4 genome

AF:

0.00000919

AC:

AN:

108781

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31581

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000299

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000185

AC:

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

Sep 28, 2022

The c.920C>T (p.P307L) alteration is located in exon 4 (coding exon 4) of the ESX1 gene. This alteration results from a C to T substitution at nucleotide position 920, causing the proline (P) at amino acid position 307 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

0.16

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.0

DANN

Benign

0.59

DEOGEN2

Benign

0.26

FATHMM_MKL

Benign

0.0079

LIST_S2

Benign

0.59

M_CAP

Benign

0.033

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.16

REVEL

Benign

0.13

Sift

Benign

0.033

Sift4G

Benign

0.42

Polyphen

0.40

Vest4

0.10

MutPred

0.29

Loss of glycosylation at P307 (P = 0.0293);

MVP

0.28

MPC

0.41

ClinPred

0.023

GERP RS

0.18

Varity_R

0.035

gMVP

0.18

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