Variant X-24207826-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003410.4(ZFX):c.911A>G(p.Asn304Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,209,622 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 129 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 13 hem., cov: 23)

Exomes 𝑓: 0.00034 ( 0 hom. 116 hem. )

Consequence

ZFX
NM_003410.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.059246242).

BS2

High Hemizygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFX	NM_003410.4 linkuse as main transcript	c.911A>G	p.Asn304Ser	missense_variant	7/10	ENST00000304543.10	NP_003401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFX	ENST00000304543.10 linkuse as main transcript	c.911A>G	p.Asn304Ser	missense_variant	7/10	5	NM_003410.4	ENSP00000304985	P1	P17010-1

Frequencies

GnomAD3 genomes

AF:

0.000304

AC:

AN:

111835

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

AN XY:

33999

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000952

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000371

Gnomad FIN

AF:

0.000333

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000362

AC:

AN:

182537

Hom.:

AF XY:

0.000373

AC XY:

AN XY:

66999

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:

0.00

Gnomad FIN exome

AF:

0.000438

Gnomad NFE exome

AF:

0.000673

Gnomad OTH exome

AF:

0.000887

GnomAD4 exome

AF:

0.000342

AC:

375

AN:

1097732

Hom.:

Cov.:

AF XY:

0.000319

AC XY:

116

AN XY:

363108

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000493

Gnomad4 NFE exome

AF:

0.000394

Gnomad4 OTH exome

AF:

0.000347

GnomAD4 genome

AF:

0.000304

AC:

AN:

111890

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

AN XY:

34064

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000372

Gnomad4 FIN

AF:

0.000333

Gnomad4 NFE

AF:

0.000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000434

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.000546

EpiControl

AF:

0.000356

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

May 31, 2022

The c.911A>G (p.N304S) alteration is located in exon 8 (coding exon 4) of the ZFX gene. This alteration results from a A to G substitution at nucleotide position 911, causing the asparagine (N) at amino acid position 304 to be replaced by a serine (S). 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

0.080

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;.;T;T;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

D;T;.;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.059

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

.;.;L;L;.

MutationTaster

Benign

0.87

D;D;D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.69

N;.;N;N;N

REVEL

Benign

0.076

Sift

Benign

0.29

T;.;T;T;T

Sift4G

Benign

0.39

T;T;T;T;T

Polyphen

0.0010

.;.;B;B;.

Vest4

0.21

MVP

0.35

MPC

0.89

ClinPred

0.050

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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