X-24179647-GTA-CTT

Variant names:

• chrX-24179647-GTA-CTT
• NM_003410.4:c.523_525delGTAinsCTT
• ZFX p.Val175Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_003410.4(ZFX):​c.523_525delGTAinsCTT​(p.Val175Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V175I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.523_525delGTAinsCTT	p.Val175Leu	missense	N/A	NP_003401.2	P17010-1
	ZFX	NM_001330327.2		c.640_642delGTAinsCTT	p.Val214Leu	missense	N/A	NP_001317256.1	P17010-3
	ZFX	NM_001178084.2		c.523_525delGTAinsCTT	p.Val175Leu	missense	N/A	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.523_525delGTAinsCTT	p.Val175Leu	missense	N/A	ENSP00000304985.5	P17010-1
	ZFX	ENST00000379177.5	TSL:1	c.523_525delGTAinsCTT	p.Val175Leu	missense	N/A	ENSP00000368475.1	P17010-1
	ZFX	ENST00000539115.5	TSL:1	c.-41-27679_-41-27677delGTAinsCTT		intron	N/A	ENSP00000438233.1	P17010-2

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-24197764;