NM_153448.4:c.986G>A

Variant names:

• chrX-104250463-C-T
• rs782262740
• NM_153448.4:c.986G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_153448.4(ESX1):​c.986G>A​(p.Arg329His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., 0 hem., cov: 15)
  • Exomes 𝑓: 0.0000062 (0 hom. 3 hem.)
  • Failed GnomAD Quality Control
• Consequence: ESX1 NM_153448.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.40
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.099225074).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESX1	NM_153448.4	MANE Select	c.986G>A	p.Arg329His	missense	Exon 4 of 4	NP_703149.1	Q8N693

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESX1	ENST00000372588.4	TSL:1 MANE Select	c.986G>A	p.Arg329His	missense	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes AF: 0.0000455 AC: 3 AN: 65886 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000180

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000617 AC: 5 AN: 810824 Hom.: 0 Cov.: 31 AF XY: 0.0000123 AC XY: 3 AN XY: 244152

African (AFR) AF: 0.00 AC: 0 AN: 16721

American (AMR) AF: 0.00 AC: 0 AN: 4581

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9281

East Asian (EAS) AF: 0.00 AC: 0 AN: 17146

South Asian (SAS) AF: 0.00 AC: 0 AN: 15070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24561

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1996

European-Non Finnish (NFE) AF: 0.00000725 AC: 5 AN: 689417

Other (OTH) AF: 0.00 AC: 0 AN: 32051

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000455 AC: 3 AN: 65886 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 15636

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000123 AC: 2 AN: 16324

American (AMR) AF: 0.000180 AC: 1 AN: 5564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1781

East Asian (EAS) AF: 0.00 AC: 0 AN: 2177

South Asian (SAS) AF: 0.00 AC: 0 AN: 1402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 81

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 34613

Other (OTH) AF: 0.00 AC: 0 AN: 810

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000509044), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.5
DANN	Benign	0.45
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-4.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.14
Sift	Benign	0.030	D
Sift4G	Benign	0.55	T
Polyphen		0.89	P
Vest4		0.054
MutPred		0.34		Loss of methylation at R329 (P = 0.0174)
MVP		0.28
MPC		0.50
ClinPred		0.17	T
GERP RS		-2.5
Varity_R		0.030
gMVP		0.069
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs782262740; hg19: chrX-103495144;