NM_003410.4:c.523G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003410.4(ZFX):​c.523G>T​(p.Val175Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,196 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. 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)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28437296).

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>T	p.Val175Leu	missense	Exon 5 of 10	NP_003401.2	P17010-1
	ZFX	NM_001330327.2		c.640G>T	p.Val214Leu	missense	Exon 6 of 11	NP_001317256.1	P17010-3
	ZFX	NM_001178084.2		c.523G>T	p.Val175Leu	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>T	p.Val175Leu	missense	Exon 5 of 10	ENSP00000304985.5	P17010-1
	ZFX	ENST00000379177.5	TSL:1	c.523G>T	p.Val175Leu	missense	Exon 6 of 11	ENSP00000368475.1	P17010-1
	ZFX	ENST00000539115.5	TSL:1	c.-41-27679G>T		intron	N/A	ENSP00000438233.1	P17010-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363552

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000119 AC: 1 AN: 842115

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

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.44	T
Polyphen		0.010	B
Vest4		0.54
MutPred		0.47		Loss of catalytic residue at V175 (P = 0.0166)
MVP		0.46
MPC		0.26
ClinPred		0.55	D
GERP RS		6.0
Varity_R		0.15
gMVP		0.58
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;