Variant 19-43966245-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000587682.6(ZNF221):c.743A>C(p.His248Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 152,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Consequence

ZNF221
ENST00000587682.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.624

Variant links:

Genes affected

ZNF221 (HGNC:13014): (zinc finger protein 221) 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, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF221 links:

ZNF221 (HGNC:):

ZNF221 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF221	NM_001297588.2 linkuse as main transcript	c.743A>C	p.His248Pro	missense_variant	5/5	ENST00000587682.6	NP_001284517.1	Q9UK13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF221	ENST00000587682.6 linkuse as main transcript	c.743A>C	p.His248Pro	missense_variant	5/5	1	NM_001297588.2	ENSP00000467367.1	Q9UK13
ZNF221	ENST00000251269.9 linkuse as main transcript	c.743A>C	p.His248Pro	missense_variant	6/6	1		ENSP00000251269.4	Q9UK13
ZNF221	ENST00000592350.5 linkuse as main transcript	c.743A>C	p.His248Pro	missense_variant	6/6	1		ENSP00000467446.1	Q9UK13
ZNF221	ENST00000622072.1 linkuse as main transcript	c.743A>C	p.His248Pro	missense_variant	4/4	2		ENSP00000477876.1	Q9UK13

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251418

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152388

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.743A>C (p.H248P) alteration is located in exon 6 (coding exon 4) of the ZNF221 gene. This alteration results from a A to C substitution at nucleotide position 743, causing the histidine (H) at amino acid position 248 to be replaced by a proline (P). 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

0.60

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.11

T;T;T;T

Eigen

Benign

-0.012

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.54

.;.;.;T

M_CAP

Benign

0.0060

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Pathogenic

3.4

M;M;M;M

MutationTaster

Benign

0.90

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-9.1

.;D;.;.

REVEL

Benign

0.16

Sift

Uncertain

0.013

.;D;.;.

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.22

MVP

0.70

MPC

0.22

ClinPred

0.65

GERP RS

1.4

Varity_R

0.16

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over