X-24207753-C-G

Position:

• chrX-24207753-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003410.4(ZFX):​c.838C>G​(p.His280Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFX	NM_003410.4	c.838C>G	p.His280Asp	missense_variant	7/10	ENST00000304543.10	NP_003401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFX	ENST00000304543.10	c.838C>G	p.His280Asp	missense_variant	7/10	5	NM_003410.4	ENSP00000304985.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2024

The c.838C>G (p.H280D) alteration is located in exon 8 (coding exon 4) of the ZFX gene. This alteration results from a C to G substitution at nucleotide position 838, causing the histidine (H) at amino acid position 280 to be replaced by an aspartic acid (D). 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	0.097
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;.;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	.;.;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;.;D;D;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D;.;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;T
Polyphen		0.99	.;.;D;D;.
Vest4		0.58
MutPred		0.65		.;.;Gain of disorder (P = 0.1164);Gain of disorder (P = 0.1164);.;
MVP		0.86
MPC		1.7
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.96

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-24225870;