19-52034481-G-T

Position:

• chr19-52034481-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014650.4(ZNF432):​c.1198C>A​(p.Pro400Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ZNF432 NM_014650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF432	NM_014650.4	c.1198C>A	p.Pro400Thr	missense_variant	5/5	ENST00000221315.10
ZNF432	NM_001322284.2	c.1198C>A	p.Pro400Thr	missense_variant	5/5
ZNF432	NM_001322285.1	c.1198C>A	p.Pro400Thr	missense_variant	5/5
ZNF432	XM_024451806.2	c.910C>A	p.Pro304Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF432	ENST00000221315.10	c.1198C>A	p.Pro400Thr	missense_variant	5/5	1	NM_014650.4	P1
ZNF432	ENST00000594154.5	c.1198C>A	p.Pro400Thr	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461760 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.1198C>A (p.P400T) alteration is located in exon 5 (coding exon 4) of the ZNF432 gene. This alteration results from a C to A substitution at nucleotide position 1198, causing the proline (P) at amino acid position 400 to be replaced by a threonine (T). 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	0.92
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.089	N
M_CAP	Benign	0.0030	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.39
MutPred		0.64		Loss of catalytic residue at P400 (P = 0.0404);Loss of catalytic residue at P400 (P = 0.0404);
MVP		0.73
MPC		0.21
ClinPred		0.98	D
GERP RS		2.7
Varity_R		0.36
gMVP		0.048

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: rs760921474; hg19: chr19-52537734;