NM_153448.4:c.943G>T

Variant names:

• chrX-104250506-C-A
• rs782703517
• NM_153448.4:c.943G>T

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.384

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 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 rank	MANE	Protein	UniProt
ESX1	NM_153448.4	c.943G>T	p.Gly315Trp	missense_variant	Exon 4 of 4	ENST00000372588.4	NP_703149.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESX1	ENST00000372588.4	c.943G>T	p.Gly315Trp	missense_variant	Exon 4 of 4	1	NM_153448.4	ENSP00000361669.4

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 14 AN: 101402 Hom.: 0 Cov.: 20 AF XY: 0.0000360 AC XY: 1 AN XY: 27782

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: 16 AN: 912107 Hom.: 0 Cov.: 32 AF XY: 0.0000430 AC XY: 12 AN XY: 279263

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: 15 AN: 101440 Hom.: 0 Cov.: 20 AF XY: 0.0000359 AC XY: 1 AN XY: 27828

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.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.095	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.38		Loss of catalytic residue at P311 (P = 0.0746);
MVP		0.55
MPC		0.48
ClinPred		0.40	T
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

Other links and lift over

dbSNP: rs782703517; hg19: chrX-103495187; COSMIC: COSV65425397;