Genetic Variant ZXDB:p.Leu74Phe (chrX-57592270-G-C) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_007157.4(ZXDB):c.222G>C(p.Leu74Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,172,386 control chromosomes in the GnomAD database, including 2 homozygotes. There are 294 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00058 ( 2 hom. 285 hem. )

Consequence

ZXDB
NM_007157.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.17

Variant links:

Genes affected

ZXDB (HGNC:13199): (zinc finger X-linked duplicated B) The ZXDB gene is one of a pair of duplicated zinc finger genes on chromosome Xp11.21 (Greig et al., 1993 [PubMed 8268913]); see also ZXDA (MIM 300235).[supplied by OMIM, Jul 2010]

ZXDB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0711042).

BP6

Variant X-57592270-G-C is Benign according to our data. Variant chrX-57592270-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2345194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZXDB	NM_007157.4 link	c.222G>C	p.Leu74Phe	missense_variant	Exon 1 of 1	ENST00000374888.3	NP_009088.1	P98169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZXDB	ENST00000374888.3 link	c.222G>C	p.Leu74Phe	missense_variant	Exon 1 of 1	6	NM_007157.4	ENSP00000364023.1		P98169

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

110439

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

33389

show subpopulations

Gnomad AFR

AF:

0.000526

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000570

Gnomad ASJ

AF:

0.000386

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000744

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00441

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000372

AC:

AN:

120835

Hom.:

AF XY:

0.000386

AC XY:

AN XY:

36305

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000172

Gnomad EAS exome

AF:

0.000115

Gnomad SAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.000104

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000577

AC:

613

AN:

1061904

Hom.:

Cov.:

AF XY:

0.000824

AC XY:

285

AN XY:

346036

show subpopulations

Gnomad4 AFR exome

AF:

0.000645

Gnomad4 AMR exome

AF:

0.000245

Gnomad4 ASJ exome

AF:

0.00258

Gnomad4 EAS exome

AF:

0.000222

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.000210

Gnomad4 NFE exome

AF:

0.000514

Gnomad4 OTH exome

AF:

0.000584

GnomAD4 genome

AF:

0.000480

AC:

AN:

110482

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

33442

show subpopulations

Gnomad4 AFR

AF:

0.000525

Gnomad4 AMR

AF:

0.000569

Gnomad4 ASJ

AF:

0.000386

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000746

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000369

Hom.:

ExAC

AF:

0.000529

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.222G>C (p.L74F) alteration is located in exon 1 (coding exon 1) of the ZXDB gene. This alteration results from a G to C substitution at nucleotide position 222, causing the leucine (L) at amino acid position 74 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ZXDB: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.11

REVEL

Benign

0.079

Sift

Benign

0.20

Sift4G

Benign

0.19

Polyphen

0.97

Vest4

0.021

MutPred

0.17

Gain of glycosylation at S72 (P = 0.1381);

MVP

0.26

MPC

1.6

ClinPred

0.029

GERP RS

2.4

Varity_R

0.091

gMVP

0.041

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