Genetic Variant ZNF226:p.Glu39Lys (chr19-44172187-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001032373.2(ZNF226):c.115G>A(p.Glu39Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00081 in 1,612,482 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00082 ( 2 hom. )

Consequence

ZNF226
NM_001032373.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.21

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF226	NM_001032373.2 link	c.115G>A	p.Glu39Lys	missense_variant	Exon 4 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.115G>A	p.Glu39Lys	missense_variant	Exon 4 of 6	1	NM_001032373.2	ENSP00000336719.5		Q9NYT6-1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000501

AC:

126

AN:

251428

AF XY:

0.000434

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000824

AC:

1203

AN:

1460128

Hom.:

Cov.:

AF XY:

0.000801

AC XY:

582

AN XY:

726380

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33432

American (AMR)

AF:

0.000202

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.000132

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00104

AC:

1160

AN:

1110922

Other (OTH)

AF:

0.000398

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152354

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41596

American (AMR)

AF:

0.000392

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000875

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.115G>A (p.E39K) alteration is located in exon 4 (coding exon 2) of the ZNF226 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the glutamic acid (E) at amino acid position 39 to be replaced by a lysine (K). 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

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

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

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.76

T;.;T;T;T;T;.;.;.;T;D;T;T;T;.;.;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.30

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

MetaSVM

Benign

-0.62

MutationAssessor

Pathogenic

3.8

.;.;H;.;.;.;.;H;H;H;.;.;.;.;H;H;.

PhyloP100

5.2

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.4

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

REVEL

Benign

0.25

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

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

Vest4

0.90, 0.69, 0.90, 0.88, 0.70

MVP

0.86

MPC

0.15

ClinPred

0.32

GERP RS

4.3

Varity_R

0.59

gMVP

0.62

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: -4

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

Publications

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19-44172187-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over