X-104250560-A-C

Position:

• chrX-104250560-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The ENST00000372588.4(ESX1):​c.889T>G​(p.Trp297Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,121,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 4 hem., cov: 21)
  • Exomes 𝑓: 0.00012 (0 hom. 41 hem.)
• Consequence: ESX1 ENST00000372588.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01248306).
• BP6: Variant X-104250560-A-C is Benign according to our data. Variant chrX-104250560-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2673250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 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	c.889T>G	p.Trp297Gly	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	c.889T>G	p.Trp297Gly	missense_variant	4/4	1	NM_153448.4	ENSP00000361669	P1

Frequencies

GnomAD3 genomes AF: 0.000239 AC: 23 AN: 96250 Hom.: 0 Cov.: 21 AF XY: 0.000153 AC XY: 4 AN XY: 26172

Gnomad AFR AF: 0.000356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000216

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: 0.000233

Gnomad OTH AF: 0.000752

GnomAD3 exomes AF: 0.000108 AC: 13 AN: 119915 Hom.: 0 AF XY: 0.000148 AC XY: 5 AN XY: 33713

Gnomad AFR exome AF: 0.000513

Gnomad AMR exome AF: 0.0000571

Gnomad ASJ exome AF: 0.000338

Gnomad EAS exome AF: 0.0000947

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 122 AN: 1025483 Hom.: 0 Cov.: 32 AF XY: 0.000127 AC XY: 41 AN XY: 323447

Gnomad4 AFR exome AF: 0.000542

Gnomad4 AMR exome AF: 0.0000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000701

Gnomad4 SAS exome AF: 0.0000471

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.000234

GnomAD4 genome AF: 0.000239 AC: 23 AN: 96279 Hom.: 0 Cov.: 21 AF XY: 0.000153 AC XY: 4 AN XY: 26199

Gnomad4 AFR AF: 0.000355

Gnomad4 AMR AF: 0.000215

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000233

Gnomad4 OTH AF: 0.000743

Alfa AF: 0.000873 Hom.: 2

ExAC AF: 0.000102 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

ESX1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.042
DANN	Benign	0.29
DEOGEN2	Benign	0.050	T
FATHMM_MKL	Benign	0.00071	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.034
Sift	Benign	1.0	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.14
MPC		0.72
ClinPred		0.0088	T
GERP RS		-5.2
Varity_R		0.056
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

Other links and lift over

dbSNP: rs782739318; hg19: chrX-103495241;