19-12430211-C-T

Variant names:

• chr19-12430211-C-T
• rs756517794
• NM_005815.5:c.1961G>A

Variant summary

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

The NM_005815.5(ZNF443):​c.1961G>A​(p.Cys654Tyr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF443 NM_005815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50

Genes affected

ZNF443 (HGNC:20878): (zinc finger protein 443) Zinc finger proteins (ZNFs) bind DNA and, through this binding, regulate gene transcription. Most ZNFs contain conserved C2H2 motifs and are classified as Kruppel-type zinc fingers. For a general description of these proteins, see ZNF91 (MIM 603971).[supplied by OMIM, Jul 2002]

ENSG00000268870 (HGNC:):

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, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF443	NM_005815.5	c.1961G>A	p.Cys654Tyr	missense_variant	Exon 4 of 4	ENST00000301547.10	NP_005806.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF443	ENST00000301547.10	c.1961G>A	p.Cys654Tyr	missense_variant	Exon 4 of 4	1	NM_005815.5	ENSP00000301547.5
ENSG00000268870	ENST00000595562.1	c.3+10701G>A		intron_variant	Intron 1 of 3	4		ENSP00000471613.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1961G>A (p.C654Y) alteration is located in exon 4 (coding exon 4) of the ZNF443 gene. This alteration results from a G to A substitution at nucleotide position 1961, causing the cysteine (C) at amino acid position 654 to be replaced by a tyrosine (Y). 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	Uncertain	0.45
BayesDel_addAF	Benign	0.0040	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0040	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.21
MutPred		0.91		Loss of methylation at K656 (P = 0.0662);
MVP		0.69
MPC		0.11
ClinPred		0.65	D
GERP RS		-0.95
Varity_R		0.28
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756517794; hg19: chr19-12541025;