19-44101137-T-G

Position:

• chr19-44101137-T-G

Variant summary

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

The NM_001321645.3(ZNF224):​c.147T>G​(p.His49Gln) 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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF224 NM_001321645.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.428

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]

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	Protein	UniProt
ZNF224	NM_001321645.3	c.147T>G	p.His49Gln	missense_variant	5/6	ENST00000693561.1	NP_001308574.1
ZNF224	NM_013398.5	c.147T>G	p.His49Gln	missense_variant	5/6		NP_037530.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF224	ENST00000693561.1	c.147T>G	p.His49Gln	missense_variant	5/6		NM_001321645.3	ENSP00000508532	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Sep 20, 2023

The c.147T>G (p.H49Q) alteration is located in exon 5 (coding exon 3) of the ZNF224 gene. This alteration results from a T to G substitution at nucleotide position 147, causing the histidine (H) at amino acid position 49 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.33
DEOGEN2	Benign	0.047	.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.11	T;T;T;T
M_CAP	Benign	0.00054	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	.;L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.7	.;D;.;.
REVEL	Benign	0.034
Sift	Uncertain	0.017	.;D;.;.
Sift4G	Benign	0.20	T;T;D;T
Polyphen		0.0010	.;B;.;.
Vest4		0.17
MutPred		0.44		Loss of catalytic residue at H49 (P = 0.0686);Loss of catalytic residue at H49 (P = 0.0686);Loss of catalytic residue at H49 (P = 0.0686);Loss of catalytic residue at H49 (P = 0.0686);
MVP		0.092
MPC		0.091
ClinPred		0.057	T
GERP RS		-1.9
Varity_R		0.028
gMVP		0.012

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 1

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: chr19-44605290;