Genetic Variant ZNF226:p.Lys53Glu (chr19-44172874-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001032373.2(ZNF226):c.157A>G(p.Lys53Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. K53Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ZNF226
NM_001032373.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0120

Publications

0 publications found

Variant links:

Genes affected

ZNF226 (HGNC:13019): (zinc finger protein 226) Predicted to enable DNA-binding transcription activator 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]

ZNF226 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11169687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF226	NM_001032373.2 link	c.157A>G	p.Lys53Glu	missense_variant	Exon 5 of 6	ENST00000337433.10	NP_001027545.1	Q9NYT6-1A0A024R0P4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF226	ENST00000337433.10 link	c.157A>G	p.Lys53Glu	missense_variant	Exon 5 of 6	1	NM_001032373.2	ENSP00000336719.5		Q9NYT6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450784

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720202

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33364

American (AMR)

AF:

0.00

AC:

AN:

43090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39464

South Asian (SAS)

AF:

0.00

AC:

AN:

83554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106712

Other (OTH)

AF:

0.00

AC:

AN:

60078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.025

.;.;T;.;.;.;.;.;.;.;.;.;.;.;T;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.018

T;.;T;T;T;T;.;.;.;T;T;T;T;T;.;.;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.1

.;.;M;.;.;.;.;M;M;M;.;.;.;.;M;M;.

PhyloP100

0.012

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

.;.;N;.;.;.;.;N;.;N;.;.;.;.;.;N;.

REVEL

Benign

0.018

Sift

Benign

0.030

.;.;D;.;.;.;.;D;.;D;.;.;.;.;.;D;.

Sift4G

Benign

0.069

T;T;T;T;T;T;T;D;D;D;T;T;T;T;T;T;T

Polyphen

0.075

.;.;B;.;.;.;.;.;.;.;.;.;.;.;B;B;.

Vest4

0.048, 0.092, 0.066, 0.084, 0.083, 0.050, 0.091

MutPred

0.48

Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);.;Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);

MVP

0.46

MPC

0.020

ClinPred

0.044

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.072

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

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

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19-44172874-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over