X-24207328-G-A

Position:

• chrX-24207328-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003410.4(ZFX):​c.649G>A​(p.Asp217Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZFX NM_003410.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

Genes affected

ZFX (HGNC:12869): (zinc finger protein X-linked) This gene on the X chromosome is structurally similar to a related gene on the Y chromosome. It encodes a member of the krueppel C2H2-type zinc-finger protein family. The full-length protein contains an acidic transcriptional activation domain (AD), a nuclear localization sequence (NLS) and a DNA binding domain (DBD) consisting of 13 C2H2-type zinc fingers. Studies in mouse embryonic and adult hematopoietic stem cells showed that this gene was required as a transcriptional regulator for self-renewal of both stem cell types, but it was dispensable for growth and differentiation of their progeny. Multiple alternatively spliced transcript variants encoding different isoforms have been identified, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFX	NM_003410.4	c.649G>A	p.Asp217Asn	missense_variant, splice_region_variant	6/10	ENST00000304543.10	NP_003401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFX	ENST00000304543.10	c.649G>A	p.Asp217Asn	missense_variant, splice_region_variant	6/10	5	NM_003410.4	ENSP00000304985.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder, x-linked, syndromic 37 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 10, 2024

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. The same missense variants were observed to have both loss of function and gain of function effects so it is unclear which mechanism is responsible for disease. These variants had reduced DNA binding and expression across a number of genes normally targeted by this transcription factor, and also increased binding to and expression of some genes not affected by wild type ZFX (PMID: 38325380). (I) 0110 - This gene is associated with X-linked disease. Heterozygous females may or may not be affected due to skewed X-inactivation, with symptoms ranging from hyperparathyroidism to a mild neurodevelopmental disorder (PMID: 38325380). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. This variant is also in a non-canonical splice region. (I) 0219 - This variant is non-coding in an alternative transcript. This variant is coding in the MANE select transcript, however, it is not coding in the most highly expressed transcript in GTEx. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. In silico predictions for abnormal splicing are conflicting. (I) 0600 - Variant is located in the annotated Zfx transcription activation family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	.;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.016	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.60
MutPred		0.90		.;Loss of disorder (P = 0.1115);Loss of disorder (P = 0.1115);
MVP		0.67
MPC		0.53
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.45
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-24225445;