Variant X-24179368-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_003410.4(ZFX):c.244A>G(p.Met82Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,098,257 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000046 ( 0 hom. 3 hem. )

Consequence

ZFX
NM_003410.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.26

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:

ZFX (HGNC:):

ZFX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2722094).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFX	NM_003410.4 linkuse as main transcript	c.244A>G	p.Met82Val	missense_variant	5/10	ENST00000304543.10	NP_003401.2	P17010-1A0A024RC04Q8WXB7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFX	ENST00000304543.10 linkuse as main transcript	c.244A>G	p.Met82Val	missense_variant	5/10	5	NM_003410.4	ENSP00000304985.5		P17010-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183476

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1098257

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363611

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000923

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.244A>G (p.M82V) alteration is located in exon 6 (coding exon 2) of the ZFX gene. This alteration results from a A to G substitution at nucleotide position 244, causing the methionine (M) at amino acid position 82 to be replaced by a valine (V). 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

0.086

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.13

.;.;T;T;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;T;.;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

.;.;L;L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.21

N;.;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.014

D;.;T;T;T

Sift4G

Uncertain

0.032

D;T;T;T;T

Polyphen

0.0020

.;.;B;B;.

Vest4

0.43, 0.32, 0.32, 0.43

MutPred

0.56

Gain of relative solvent accessibility (P = 0.0522);.;Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);

MVP

0.72

MPC

0.26

ClinPred

0.11

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.11

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

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