Genetic Variant ZNF222:p.Ala13Val (chr19-44025474-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001129996.2(ZNF222):c.38C>T(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ZNF222
NM_001129996.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.50

Variant links:

Genes affected

ZNF222 (HGNC:13015): (zinc finger protein 222) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF222 links:

ENSG00000267022 (HGNC:):

ENSG00000267022 links:

ZNF222-DT (HGNC:55310): (ZNF222 divergent transcript)

ZNF222-DT links:

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ACMG classification

Classification was made for transcript

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=0.047478765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF222	NM_001129996.2 link	c.38C>T	p.Ala13Val	missense_variant	Exon 1 of 4	ENST00000391960.4	NP_001123468.1	Q9UK12-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF222	ENST00000391960.4 link	c.38C>T	p.Ala13Val	missense_variant	Exon 1 of 4	1	NM_001129996.2	ENSP00000375822.2		Q9UK12-2
ENSG00000267022	ENST00000591793.1 link	n.38C>T		non_coding_transcript_exon_variant	Exon 1 of 11	2		ENSP00000467018.1		K7ENM7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1397236

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31460

American (AMR)

AF:

0.00

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24980

East Asian (EAS)

AF:

0.00

AC:

AN:

35688

South Asian (SAS)

AF:

0.0000127

AC:

AN:

79024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078108

Other (OTH)

AF:

0.00

AC:

AN:

57896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.38C>T (p.A13V) alteration is located in exon 1 (coding exon 1) of the ZNF222 gene. This alteration results from a C to T substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a valine (V). 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

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.31

(source)

DANN

Benign

0.78

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.13

T;T

M_CAP

Benign

0.0011

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.93

PhyloP100

-1.5

PrimateAI

Benign

0.42

PROVEAN

Benign

0.29

.;N

REVEL

Benign

0.0030

Sift

Benign

0.27

.;T

Sift4G

Benign

0.68

T;T

Vest4

0.051

MutPred

0.19

Loss of ubiquitination at K8 (P = 0.077);Loss of ubiquitination at K8 (P = 0.077);

MVP

0.055

MPC

0.058

ClinPred

0.12

GERP RS

-2.2

PromoterAI

-0.052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.028

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

chr19-44025474-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over