X-24179564-T-G

Variant names:

• chrX-24179564-T-G
• rs747616979
• NM_003410.4:c.440T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003410.4(ZFX):​c.440T>G​(p.Val147Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,228 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0760

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06863788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFX	NM_003410.4	c.440T>G	p.Val147Gly	missense_variant	Exon 5 of 10	ENST00000304543.10	NP_003401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFX	ENST00000304543.10	c.440T>G	p.Val147Gly	missense_variant	Exon 5 of 10	5	NM_003410.4	ENSP00000304985.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183446 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67890

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 SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.12	.;T;T;.
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.62	T;.;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.069	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	.;L;L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.18	.;N;N;N
REVEL	Benign	0.033
Sift	Uncertain	0.0050	.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.032	.;B;B;.
Vest4		0.12
MutPred		0.46		.;Loss of stability (P = 0.043);Loss of stability (P = 0.043);Loss of stability (P = 0.043);
MVP		0.043
MPC		0.33
ClinPred		0.033	T
GERP RS		1.2
Varity_R		0.15
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs747616979; hg19: chrX-24197681;