Variant chr19-58477229-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017908.4(ZNF446):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,573,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

ZNF446
NM_017908.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.166

Variant links:

Genes affected

ZNF446 (HGNC:21036): (zinc finger protein 446) Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ZNF446 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011755377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4 linkuse as main transcript	c.11C>T	p.Pro4Leu	missense_variant	2/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1 linkuse as main transcript	c.11C>T	p.Pro4Leu	missense_variant	1/6		NP_001291382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF446	ENST00000594369.6 linkuse as main transcript	c.11C>T	p.Pro4Leu	missense_variant	2/7	1	NM_017908.4	ENSP00000472802	P1	Q9NWS9-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000351

AC:

AN:

225354

Hom.:

AF XY:

0.000352

AC XY:

AN XY:

122114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000586

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000377

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000233

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

AF:

0.000259

AC:

368

AN:

1421620

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

188

AN XY:

703044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000743

Gnomad4 ASJ exome

AF:

0.00401

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000731

Gnomad4 FIN exome

AF:

0.0000200

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000548

GnomAD4 genome

AF:

0.000236

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000452

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000330

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, 2023

The c.11C>T (p.P4L) alteration is located in exon 2 (coding exon 1) of the ZNF446 gene. This alteration results from a C to T substitution at nucleotide position 11, causing the proline (P) at amino acid position 4 to be replaced by a leucine (L). 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

Benign

0.14

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T;T;.;.;.

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.82

T;T;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

.;.;M;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.2

.;.;.;.;D;.

REVEL

Benign

0.073

Sift

Uncertain

0.0050

.;.;.;.;D;.

Sift4G

Uncertain

0.022

D;D;D;D;D;D

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.36

MVP

0.22

MPC

0.23

ClinPred

0.10

GERP RS

3.7

Varity_R

0.12

gMVP

0.57

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