chr19-44108078-A-G

Variant names:

• chr19-44108078-A-G
• rs3746319
• NM_001321645.3:c.1918A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001321645.3(ZNF224):​c.1918A>G​(p.Lys640Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.785 in 1,613,870 control chromosomes in the GnomAD database, including 506,347 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.70 (38564 hom., cov: 32)
  • Exomes 𝑓: 0.79 (467783 hom.)
• Consequence: ZNF224 NM_001321645.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.558
• Publications: 55 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5387097E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF224	NM_001321645.3	MANE Select	c.1918A>G	p.Lys640Glu	missense	Exon 6 of 6	NP_001308574.1
	ZNF224	NM_013398.5		c.1918A>G	p.Lys640Glu	missense	Exon 6 of 6	NP_037530.2
	ZNF225-AS1	NR_033341.1		n.622T>C		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF224	ENST00000693561.1	MANE Select	c.1918A>G	p.Lys640Glu	missense	Exon 6 of 6	ENSP00000508532.1
	ZNF224	ENST00000336976.10	TSL:1	c.1918A>G	p.Lys640Glu	missense	Exon 6 of 6	ENSP00000337368.5
	ZNF225-AS1	ENST00000592946.1	TSL:1	n.584T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.697 AC: 105851 AN: 151880 Hom.: 38550 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.724

GnomAD2 exomes AF: 0.710 AC: 178451 AN: 251408 AF XY: 0.723

Gnomad AFR exome AF: 0.511

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.770

Gnomad NFE exome AF: 0.824

Gnomad OTH exome AF: 0.756

GnomAD4 exome AF: 0.794 AC: 1160511 AN: 1461870 Hom.: 467783 Cov.: 77 AF XY: 0.793 AC XY: 576768 AN XY: 727238

African (AFR) AF: 0.506 AC: 16937 AN: 33478

American (AMR) AF: 0.490 AC: 21934 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 20197 AN: 26136

East Asian (EAS) AF: 0.545 AC: 21633 AN: 39700

South Asian (SAS) AF: 0.689 AC: 59396 AN: 86258

European-Finnish (FIN) AF: 0.770 AC: 41116 AN: 53418

Middle Eastern (MID) AF: 0.756 AC: 4361 AN: 5768

European-Non Finnish (NFE) AF: 0.835 AC: 928721 AN: 1111996

Other (OTH) AF: 0.765 AC: 46216 AN: 60396

GnomAD4 genome AF: 0.697 AC: 105896 AN: 152000 Hom.: 38564 Cov.: 32 AF XY: 0.689 AC XY: 51159 AN XY: 74286

African (AFR) AF: 0.519 AC: 21511 AN: 41416

American (AMR) AF: 0.568 AC: 8678 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2716 AN: 3472

East Asian (EAS) AF: 0.553 AC: 2850 AN: 5152

South Asian (SAS) AF: 0.683 AC: 3293 AN: 4822

European-Finnish (FIN) AF: 0.767 AC: 8109 AN: 10568

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56335 AN: 67984

Other (OTH) AF: 0.722 AC: 1525 AN: 2112

Alfa AF: 0.783 Hom.: 181988

Bravo AF: 0.673

TwinsUK AF: 0.838 AC: 3108

ALSPAC AF: 0.841 AC: 3242

ESP6500AA AF: 0.509 AC: 2243

ESP6500EA AF: 0.819 AC: 7041

ExAC AF: 0.715 AC: 86831

Asia WGS AF: 0.590 AC: 2056 AN: 3478

EpiCase AF: 0.831

EpiControl AF: 0.829

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.72
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.085	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.56
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.015
Sift	Benign	0.62	T
Sift4G	Benign	0.21	T
Polyphen		0.030	B
Vest4		0.020
MPC		0.13
ClinPred		0.0014	T
GERP RS		-4.3
Varity_R		0.044
gMVP		0.015
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs3746319; hg19: chr19-44612231; COSMIC: COSV107415816; COSMIC: COSV107415816;