19-52034267-C-T

Variant names:

• chr19-52034267-C-T
• rs183343359
• NM_014650.4:c.1412G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014650.4(ZNF432):​c.1412G>A​(p.Arg471Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,030 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. R471W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ZNF432 NM_014650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.37

Genes affected

ZNF432 (HGNC:20810): (zinc finger protein 432) 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. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055790246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF432	NM_014650.4	c.1412G>A	p.Arg471Gln	missense_variant	Exon 5 of 5	ENST00000221315.10	NP_055465.1
ZNF432	NM_001322284.2	c.1412G>A	p.Arg471Gln	missense_variant	Exon 5 of 5		NP_001309213.1
ZNF432	NM_001322285.1	c.1412G>A	p.Arg471Gln	missense_variant	Exon 5 of 5		NP_001309214.1
ZNF432	XM_024451806.2	c.1124G>A	p.Arg375Gln	missense_variant	Exon 2 of 2		XP_024307574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF432	ENST00000221315.10	c.1412G>A	p.Arg471Gln	missense_variant	Exon 5 of 5	1	NM_014650.4	ENSP00000221315.4
ZNF432	ENST00000594154.5	c.1412G>A	p.Arg471Gln	missense_variant	Exon 5 of 5	1		ENSP00000470488.1

Frequencies

GnomAD3 genomes AF: 0.0000662 AC: 10 AN: 151148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000590

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251172 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135764

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461756 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000661 AC: 10 AN: 151274 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3 AN XY: 73930

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000591

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1412G>A (p.R471Q) alteration is located in exon 5 (coding exon 4) of the ZNF432 gene. This alteration results from a G to A substitution at nucleotide position 1412, causing the arginine (R) at amino acid position 471 to be replaced by a glutamine (Q). 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	Pathogenic	0.70
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0037	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.00010	N
LIST_S2	Benign	0.23	.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.21	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.14	.;N
REVEL	Benign	0.063
Sift	Benign	0.79	.;T
Sift4G	Benign	0.36	T;T
Polyphen		0.96	D;D
Vest4		0.25
MVP		0.19
MPC		0.30
ClinPred		0.091	T
GERP RS		0.57
Varity_R		0.069
gMVP		0.033

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

Other links and lift over

dbSNP: rs183343359; hg19: chr19-52537520; COSMIC: COSV105019672; COSMIC: COSV105019672;