chrX-104250461-C-G

Variant names:

• chrX-104250461-C-G
• rs1247155340
• NM_153448.4:c.988G>C

Variant summary

Our verdict is Likely benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000050 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.000036 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: ESX1 NM_153448.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.59
• Publications: 0 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=0.08334744).

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.988G>C	p.Val330Leu	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.988G>C	p.Val330Leu	missense	Exon 4 of 4	ENSP00000361669.4	Q8N693

Frequencies

GnomAD3 genomes AF: 0.0000500 AC: 5 AN: 100088 Hom.: 0 Cov.: 19

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: 30 AN: 826493 Hom.: 0 Cov.: 32 AF XY: 0.00000799 AC XY: 2 AN XY: 250303

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

African (AFR) AF: 0.0000587 AC: 1 AN: 17035

American (AMR) AF: 0.00176 AC: 9 AN: 5113

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9596

East Asian (EAS) AF: 0.000113 AC: 2 AN: 17681

South Asian (SAS) AF: 0.0000636 AC: 1 AN: 15733

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2017

European-Non Finnish (NFE) AF: 0.0000214 AC: 15 AN: 701022

Other (OTH) AF: 0.0000608 AC: 2 AN: 32888

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000287718), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000499 AC: 5 AN: 100106 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 26092

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

African (AFR) AF: 0.0000360 AC: 1 AN: 27770

American (AMR) AF: 0.000111 AC: 1 AN: 8974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2484

East Asian (EAS) AF: 0.00 AC: 0 AN: 3016

South Asian (SAS) AF: 0.00 AC: 0 AN: 2161

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4203

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 177

European-Non Finnish (NFE) AF: 0.0000608 AC: 3 AN: 49362

Other (OTH) AF: 0.00 AC: 0 AN: 1335

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00684762), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000759 Hom.: 1

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	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.15
DANN	Benign	0.49
DEOGEN2	Benign	0.059	T
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		-1.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.12
Sift	Benign	0.27	T
Sift4G	Benign	0.65	T
Polyphen		0.0010	B
Vest4		0.043
MutPred		0.29		Loss of methylation at R329 (P = 0.0952)
MVP		0.29
MPC		0.40
ClinPred		0.048	T
GERP RS		-1.1
Varity_R		0.052
gMVP		0.081
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: rs1247155340; hg19: chrX-103495142; COSMIC: COSV99055923;