X-24179647-G-A

Variant names:

• chrX-24179647-G-A
• rs758942664
• NM_003410.4:c.523G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003410.4(ZFX):​c.523G>A​(p.Val175Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,098,195 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22
• Publications: 1 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.

• 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 intellectual developmental disorder, X-linked, syndromic 37.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18845326).

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.523G>A	p.Val175Ile	missense	Exon 5 of 10	NP_003401.2	P17010-1
	ZFX	NM_001330327.2		c.640G>A	p.Val214Ile	missense	Exon 6 of 11	NP_001317256.1	P17010-3
	ZFX	NM_001178084.2		c.523G>A	p.Val175Ile	missense	Exon 3 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.523G>A	p.Val175Ile	missense	Exon 5 of 10	ENSP00000304985.5	P17010-1
	ZFX	ENST00000379177.5	TSL:1	c.523G>A	p.Val175Ile	missense	Exon 6 of 11	ENSP00000368475.1	P17010-1
	ZFX	ENST00000539115.5	TSL:1	c.-41-27679G>A		intron	N/A	ENSP00000438233.1	P17010-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183353 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098195 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363551

African (AFR) AF: 0.0000379 AC: 1 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000237 AC: 2 AN: 842114

Other (OTH) AF: 0.00 AC: 0 AN: 46098

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	N
PhyloP100		5.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.057
Sift	Benign	0.42	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.35
MutPred		0.47		Loss of catalytic residue at V175 (P = 0.0232)
MVP		0.25
MPC		0.20
ClinPred		0.22	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.43
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs758942664; hg19: chrX-24197764;