rs3746319

Positions:

• chr19-44108078-A-C
• chr19-44108078-A-G

Variant summary

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

The NM_001321645.3(ZNF224):​c.1918A>C​(p.Lys640Gln) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K640E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF224 NM_001321645.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.558

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

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=0.057696372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF224	NM_001321645.3	c.1918A>C	p.Lys640Gln	missense_variant	6/6	ENST00000693561.1	NP_001308574.1
ZNF225-AS1	NR_033341.1	n.622T>G		non_coding_transcript_exon_variant	2/2
ZNF224	NM_013398.5	c.1918A>C	p.Lys640Gln	missense_variant	6/6		NP_037530.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF224	ENST00000693561.1	c.1918A>C	p.Lys640Gln	missense_variant	6/6		NM_001321645.3	ENSP00000508532	P1
ZNF225-AS1	ENST00000661725.1	n.622T>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 77

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.1
DANN	Benign	0.38
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.00059	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.017
Sift	Benign	1.0	T
Sift4G	Benign	0.43	T
Polyphen		0.030	B
Vest4		0.024
MutPred		0.32		Loss of ubiquitination at K640 (P = 0.0309);
MVP		0.10
MPC		0.12
ClinPred		0.022	T
GERP RS		-4.3
Varity_R		0.041
gMVP		0.018

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: rs3746319; hg19: chr19-44612231;