19-52033839-C-G

Variant names:

• chr19-52033839-C-G
• NM_014650.4:c.1840G>C

Variant summary

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

The NM_014650.4(ZNF432):​c.1840G>C​(p.Val614Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF432 NM_014650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.69

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=0.04574144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF432	NM_014650.4	c.1840G>C	p.Val614Leu	missense_variant	Exon 5 of 5	ENST00000221315.10	NP_055465.1
ZNF432	NM_001322284.2	c.1840G>C	p.Val614Leu	missense_variant	Exon 5 of 5		NP_001309213.1
ZNF432	NM_001322285.1	c.1840G>C	p.Val614Leu	missense_variant	Exon 5 of 5		NP_001309214.1
ZNF432	XM_024451806.2	c.1552G>C	p.Val518Leu	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.1840G>C	p.Val614Leu	missense_variant	Exon 5 of 5	1	NM_014650.4	ENSP00000221315.4
ZNF432	ENST00000594154.5	c.1840G>C	p.Val614Leu	missense_variant	Exon 5 of 5	1		ENSP00000470488.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1840G>C (p.V614L) alteration is located in exon 5 (coding exon 4) of the ZNF432 gene. This alteration results from a G to C substitution at nucleotide position 1840, causing the valine (V) at amino acid position 614 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	Benign	0.30
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00039	N
LIST_S2	Benign	0.11	.;T
M_CAP	Benign	0.00049	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.53	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.78	.;N
REVEL	Benign	0.012
Sift	Benign	0.54	.;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0010	B;B
Vest4		0.11
MutPred		0.27		Loss of MoRF binding (P = 0.0909);Loss of MoRF binding (P = 0.0909);
MVP		0.11
MPC		0.046
ClinPred		0.025	T
GERP RS		-0.68
Varity_R		0.033
gMVP		0.062

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-52537092;