Genetic Variant ZFX:p.Arg292Cys (chrX-24207789-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003410.4(ZFX):c.874C>T(p.Arg292Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,766 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

ZFX
NM_003410.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFX	NM_003410.4 link	c.874C>T	p.Arg292Cys	missense_variant	Exon 7 of 10	ENST00000304543.10	NP_003401.2	P17010-1A0A024RC04Q8WXB7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFX	ENST00000304543.10 link	c.874C>T	p.Arg292Cys	missense_variant	Exon 7 of 10	5	NM_003410.4	ENSP00000304985.5		P17010-1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111766

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33942

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183263

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67711

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000182

AC:

AN:

1097653

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363035

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111766

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33942

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000447

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.874C>T (p.R292C) alteration is located in exon 8 (coding exon 4) of the ZFX gene. This alteration results from a C to T substitution at nucleotide position 874, causing the arginine (R) at amino acid position 292 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

.;.;T;T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;.;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Uncertain

0.53

D;D;D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.6

.;.;M;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.7

D;.;D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.016

D;.;D;D;D

Sift4G

Uncertain

0.041

D;D;D;D;D

Polyphen

0.99

.;.;D;D;.

Vest4

0.36

MutPred

0.80

.;.;Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);.;

MVP

0.52

MPC

1.4

ClinPred

0.76

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over