chr19-52034495-T-C

Position:

• chr19-52034495-T-C

Variant summary

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

The NM_014650.4(ZNF432):​c.1184A>G​(p.His395Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 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: 6.8e-7 (0 hom.)
• Consequence: ZNF432 NM_014650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

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.1184A>G	p.His395Arg	missense_variant	5/5	ENST00000221315.10
ZNF432	NM_001322284.2	c.1184A>G	p.His395Arg	missense_variant	5/5
ZNF432	NM_001322285.1	c.1184A>G	p.His395Arg	missense_variant	5/5
ZNF432	XM_024451806.2	c.896A>G	p.His299Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF432	ENST00000221315.10	c.1184A>G	p.His395Arg	missense_variant	5/5	1	NM_014650.4	P1
ZNF432	ENST00000594154.5	c.1184A>G	p.His395Arg	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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 05, 2024

The c.1184A>G (p.H395R) alteration is located in exon 5 (coding exon 4) of the ZNF432 gene. This alteration results from a A to G substitution at nucleotide position 1184, causing the histidine (H) at amino acid position 395 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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.63	.;T
M_CAP	Benign	0.0022	T
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.8	.;D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.49
MutPred		0.78		Gain of MoRF binding (P = 0.0162);Gain of MoRF binding (P = 0.0162);
MVP		0.46
MPC		0.32
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.83
gMVP		0.17

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: rs370952582; hg19: chr19-52537748;