19-52033751-T-A

Position:

• chr19-52033751-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014650.4(ZNF432):​c.1928A>T​(p.His643Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000483 in 1,449,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ZNF432 NM_014650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF432	NM_014650.4	c.1928A>T	p.His643Leu	missense_variant	5/5	ENST00000221315.10
ZNF432	NM_001322284.2	c.1928A>T	p.His643Leu	missense_variant	5/5
ZNF432	NM_001322285.1	c.1928A>T	p.His643Leu	missense_variant	5/5
ZNF432	XM_024451806.2	c.1640A>T	p.His547Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF432	ENST00000221315.10	c.1928A>T	p.His643Leu	missense_variant	5/5	1	NM_014650.4	P1
ZNF432	ENST00000594154.5	c.1928A>T	p.His643Leu	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1449774 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 720930

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: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Nov 09, 2023

The c.1928A>T (p.H643L) alteration is located in exon 5 (coding exon 4) of the ZNF432 gene. This alteration results from a A to T substitution at nucleotide position 1928, causing the histidine (H) at amino acid position 643 to be replaced by a leucine (L). 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	0.80
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.034	N
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.67	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.63
MutPred		0.76		Loss of disorder (P = 0.0309);Loss of disorder (P = 0.0309);
MVP		0.97
MPC		0.32
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.71
gMVP		0.32

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: rs138563719; hg19: chr19-52537004;