chrX-24207796-C-G

Variant names:

• chrX-24207796-C-G
• rs1937706244
• NM_003410.4:c.881C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003410.4(ZFX):​c.881C>G​(p.Pro294Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• Publications: 0 publications found

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]

ZFX Gene-Disease associations (from GenCC):

• X-linked syndromic complex neurodevelopmental disorder

  Inheritance: XL Classification: STRONG Submitted by: ClinGen
• intellectual developmental disorder, X-linked, syndromic 37

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000304417 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.1463 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked syndromic complex neurodevelopmental disorder, intellectual developmental disorder, X-linked, syndromic 37.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003410.4. 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
	ZFX	NM_003410.4	MANE Select	c.881C>G	p.Pro294Arg	missense	Exon 7 of 10	NP_003401.2	P17010-1
	ZFX	NM_001330327.2		c.998C>G	p.Pro333Arg	missense	Exon 8 of 11	NP_001317256.1	P17010-3
	ZFX	NM_001178084.2		c.881C>G	p.Pro294Arg	missense	Exon 5 of 8	NP_001171555.1	P17010-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFX	ENST00000304543.10	TSL:5 MANE Select	c.881C>G	p.Pro294Arg	missense	Exon 7 of 10	ENSP00000304985.5	P17010-1
	ZFX	ENST00000379177.5	TSL:1	c.881C>G	p.Pro294Arg	missense	Exon 8 of 11	ENSP00000368475.1	P17010-1
	ZFX	ENST00000539115.5	TSL:1	c.194C>G	p.Pro65Arg	missense	Exon 3 of 6	ENSP00000438233.1	P17010-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.35
Sift	Benign	0.082	T
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.44
MutPred		0.69		Gain of MoRF binding (P = 0.0084)
MVP		0.53
MPC		2.1
ClinPred		0.85	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.93
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1937706244; hg19: chrX-24225913;