chr19-44106768-G-A

Variant names:

• chr19-44106768-G-A
• NM_001321645.3:c.608G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001321645.3(ZNF224):​c.608G>A​(p.Cys203Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,170 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF224 NM_001321645.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.62
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052180767).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321645.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF224	NM_001321645.3	MANE Select	c.608G>A	p.Cys203Tyr	missense	Exon 6 of 6	NP_001308574.1	Q9NZL3
	ZNF224	NM_013398.5		c.608G>A	p.Cys203Tyr	missense	Exon 6 of 6	NP_037530.2	Q9NZL3
	ZNF225-AS1	NR_033341.1		n.1932C>T		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF224	ENST00000693561.1	MANE Select	c.608G>A	p.Cys203Tyr	missense	Exon 6 of 6	ENSP00000508532.1	Q9NZL3
	ZNF224	ENST00000336976.10	TSL:1	c.608G>A	p.Cys203Tyr	missense	Exon 6 of 6	ENSP00000337368.5	Q9NZL3
	ZNF225-AS1	ENST00000592946.1	TSL:1	n.1894C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461170 Hom.: 0 Cov.: 88 AF XY: 0.00000138 AC XY: 1 AN XY: 726894

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111588

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.34
DANN	Benign	0.49
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.061	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		-3.6
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Uncertain	0.039	D
Polyphen		0.44	B
Vest4		0.12
MutPred		0.54		Loss of methylation at K202 (P = 0.022)
MVP		0.067
MPC		0.19
ClinPred		0.092	T
GERP RS		-6.9
Varity_R		0.045
gMVP		0.013
Mutation Taster		=99/1	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: chr19-44610921;