Genetic Variant NM_007157.4:c.232A>C (chrX-57592280-A-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_007157.4(ZXDB):c.232A>C(p.Thr78Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,179,841 control chromosomes in the GnomAD database, including 2 homozygotes. There are 293 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00054 ( 2 hom. 287 hem. )

Consequence

ZXDB
NM_007157.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.45

Publications

3 publications found

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 was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021636188).

BP6

Variant X-57592280-A-C is Benign according to our data. Variant chrX-57592280-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2660723.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZXDB	NM_007157.4	MANE Select	c.232A>C	p.Thr78Pro	missense	Exon 1 of 1	NP_009088.1	P98169

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZXDB	ENST00000374888.3	TSL:6 MANE Select	c.232A>C	p.Thr78Pro	missense	Exon 1 of 1	ENSP00000364023.1	P98169

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

110140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000377

Gnomad ASJ

AF:

0.000769

Gnomad EAS

AF:

0.000590

Gnomad SAS

AF:

0.000748

Gnomad FIN

AF:

0.000170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000381

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000290

AC:

AN:

130895

AF XY:

0.000266

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000823

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000409

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000269

Gnomad OTH exome

AF:

0.000621

GnomAD4 exome

AF:

0.000541

AC:

579

AN:

1069666

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

287

AN XY:

349398

show subpopulations

African (AFR)

AF:

0.000462

AC:

AN:

23785

American (AMR)

AF:

0.000267

AC:

AN:

33678

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

18554

East Asian (EAS)

AF:

0.000502

AC:

AN:

27887

South Asian (SAS)

AF:

0.00143

AC:

AN:

51868

European-Finnish (FIN)

AF:

0.000149

AC:

AN:

33666

Middle Eastern (MID)

AF:

0.000705

AC:

AN:

2838

European-Non Finnish (NFE)

AF:

0.000466

AC:

388

AN:

832541

Other (OTH)

AF:

0.000714

AC:

AN:

44849

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000381

AC:

AN:

110175

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

AN XY:

33145

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000364

AC:

AN:

30229

American (AMR)

AF:

0.000377

AC:

AN:

10608

Ashkenazi Jewish (ASJ)

AF:

0.000769

AC:

AN:

2601

East Asian (EAS)

AF:

0.000592

AC:

AN:

3380

South Asian (SAS)

AF:

0.000752

AC:

AN:

2661

European-Finnish (FIN)

AF:

0.000170

AC:

AN:

5866

Middle Eastern (MID)

AF:

0.00

AC:

AN:

203

European-Non Finnish (NFE)

AF:

0.000381

AC:

AN:

52468

Other (OTH)

AF:

0.00

AC:

AN:

1497

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000000111022), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.346

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000797

Hom.:

ExAC

AF:

0.000339

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.95

BayesDel_noAF

Benign

-1.2

CADD

Benign

0.92

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.0043

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.12

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.1

PhyloP100

-2.4

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.040

REVEL

Benign

0.017

Sift

Benign

1.0

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.016

MVP

0.043

MPC

1.3

ClinPred

0.023

GERP RS

0.49

PromoterAI

0.0028

Neutral

(source)

Varity_R

0.13

gMVP

0.031

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over