X-24207759-G-A

Position:

• chrX-24207759-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003410.4(ZFX):​c.844G>A​(p.Val282Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 112,249 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2675982).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFX	NM_003410.4	c.844G>A	p.Val282Ile	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.844G>A	p.Val282Ile	missense_variant	7/10	5	NM_003410.4	ENSP00000304985	P1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112249 Hom.: 0 Cov.: 23 AF XY: 0.0000581 AC XY: 2 AN XY: 34395

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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 Cov.: 31

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112249 Hom.: 0 Cov.: 23 AF XY: 0.0000581 AC XY: 2 AN XY: 34395

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 11, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	.;.;M;M;.
MutationTaster	Benign	0.89	D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.34	N;.;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.019	D;.;D;D;D
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.51	.;.;P;P;.
Vest4		0.23
MutPred		0.54		.;.;Loss of catalytic residue at V282 (P = 0.0598);Loss of catalytic residue at V282 (P = 0.0598);.;
MVP		0.42
MPC		1.2
ClinPred		0.72	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.64

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: rs966709575; hg19: chrX-24225876;