Genetic Variant ZXDC:p.Val792Ile (chr3-126441785-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025112.5(ZXDC):c.2374G>A(p.Val792Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,602,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

ZXDC
NM_025112.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.446

Publications

0 publications found

Variant links:

Genes affected

ZXDC (HGNC:28160): (ZXD family zinc finger C) Enables C2H2 zinc finger domain binding activity; LRR domain binding activity; and transcription coactivator activity. Involved in positive regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZXDC links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054752618).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025112.5. 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
	ZXDC	NM_025112.5	MANE Select	c.2374G>A	p.Val792Ile	missense	Exon 8 of 10	NP_079388.3
	ZXDC	NR_104249.2		n.2580G>A		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZXDC	ENST00000389709.8	TSL:1 MANE Select	c.2374G>A	p.Val792Ile	missense	Exon 8 of 10	ENSP00000374359.3	Q2QGD7-1
ZXDC	ENST00000514463.1	TSL:1	n.1625G>A		non_coding_transcript_exon	Exon 1 of 2
ZXDC	ENST00000515545.5	TSL:1	n.*421G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000426532.1	H0YAA9

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000844

AC:

AN:

237014

AF XY:

0.00000775

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000428

AC:

AN:

1450292

Hom.:

Cov.:

AF XY:

0.0000457

AC XY:

AN XY:

721322

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

33028

American (AMR)

AF:

0.00

AC:

AN:

42934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25506

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39540

South Asian (SAS)

AF:

0.000142

AC:

AN:

84458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.0000361

AC:

AN:

1108088

Other (OTH)

AF:

0.000133

AC:

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.8

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.025

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.65

M_CAP

Benign

0.0015

MetaRNN

Benign

0.055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

PhyloP100

-0.45

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.39

REVEL

Benign

0.059

Sift

Benign

0.11

Sift4G

Uncertain

0.040

Polyphen

0.011

Vest4

0.092

MutPred

0.27

Loss of catalytic residue at V792 (P = 0.0269)

MVP

0.040

MPC

0.077

ClinPred

0.036

GERP RS

-0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.067

gMVP

0.051

Mutation Taster

=95/5

polymorphism

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over