chr19-44107404-G-A

Variant names:

• chr19-44107404-G-A
• NM_001321645.3:c.1244G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001321645.3(ZNF224):​c.1244G>A​(p.Cys415Tyr) 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. 16/22 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: ZNF224 NM_001321645.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.627
• Publications: 0 publications found

Genes affected

ZNF224 (HGNC:13017): (zinc finger protein 224) This gene encodes a member of the Krueppel C2H2-type zinc-finger family of proteins. The encoded protein represses transcription of the aldolase A gene, which encodes a key enzyme in glycolysis. The encoded zinc-finger protein may also function as a transcriptional co-activator with Wilms' tumor protein 1 to regulate apoptotic genes in leukemia. [provided by RefSeq, Jul 2016]

ZNF225-AS1 (HGNC:55916): (ZNF225 and ZNF224 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08001417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF224	NM_001321645.3	c.1244G>A	p.Cys415Tyr	missense_variant	Exon 6 of 6	ENST00000693561.1	NP_001308574.1
ZNF224	NM_013398.5	c.1244G>A	p.Cys415Tyr	missense_variant	Exon 6 of 6		NP_037530.2
ZNF225-AS1	NR_033341.1	n.1296C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF224	ENST00000693561.1	c.1244G>A	p.Cys415Tyr	missense_variant	Exon 6 of 6		NM_001321645.3	ENSP00000508532.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 81

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1244G>A (p.C415Y) alteration is located in exon 6 (coding exon 4) of the ZNF224 gene. This alteration results from a G to A substitution at nucleotide position 1244, causing the cysteine (C) at amino acid position 415 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	Benign	0.21
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.66
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.63
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.030
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.29	B
Vest4		0.12
MutPred		0.50		Gain of phosphorylation at C415 (P = 0.0563);
MVP		0.20
MPC		0.20
ClinPred		0.22	T
GERP RS		1.8
Varity_R		0.056
gMVP		0.039
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

hg19: chr19-44611557;