Genetic Variant ZNF429:p.Pro62Arg (chr19-21530643-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001001415.4(ZNF429):c.185C>G(p.Pro62Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P62H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ZNF429
NM_001001415.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.395

Variant links:

Genes affected

ZNF429 (HGNC:20817): (zinc finger protein 429) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF429 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15309116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF429	NM_001001415.4 link	c.185C>G	p.Pro62Arg	missense_variant	Exon 3 of 4	ENST00000358491.9	NP_001001415.2	Q86V71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF429	ENST00000358491.9 link	c.185C>G	p.Pro62Arg	missense_variant	Exon 3 of 4	3	NM_001001415.4	ENSP00000351280.3	Q86V71
ZNF429	ENST00000597078.5 link	c.185C>G	p.Pro62Arg	missense_variant	Exon 3 of 6	1		ENSP00000470300.1	M0QZ47
ZNF429	ENST00000594022.1 link	n.570C>G		non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

249790

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1459668

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185C>G (p.P62R) alteration is located in exon 3 (coding exon 3) of the ZNF429 gene. This alteration results from a C to G substitution at nucleotide position 185, causing the proline (P) at amino acid position 62 to be replaced by an arginine (R). 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

0.18

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.58

T;T;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.;.

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.9

D;.;.

REVEL

Benign

0.024

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.16

MutPred

0.36

Loss of catalytic residue at P62 (P = 0.0083);Loss of catalytic residue at P62 (P = 0.0083);Loss of catalytic residue at P62 (P = 0.0083);

MVP

0.58

MPC

0.21

ClinPred

0.42

GERP RS

0.23

Varity_R

0.22

gMVP

0.020

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