Variant 19-58477300-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017908.4(ZNF446):c.82C>T(p.Arg28Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ZNF446
NM_017908.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.388

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41666216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4 linkuse as main transcript	c.82C>T	p.Arg28Cys	missense_variant	2/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1 linkuse as main transcript	c.82C>T	p.Arg28Cys	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.82C>T	p.Arg28Cys	missense_variant	2/7	1	NM_017908.4	ENSP00000472802	P1	Q9NWS9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250284

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460738

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726658

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

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

Jul 28, 2021

The c.82C>T (p.R28C) 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 82, causing the arginine (R) at amino acid position 28 to be replaced by a cysteine (C). 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

0.23

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

T;T;T;.;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.046

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.42

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;.;M;.;.;M

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

.;.;.;.;D;.

REVEL

Benign

0.067

Sift

Uncertain

0.019

.;.;.;.;D;.

Sift4G

Uncertain

0.022

D;T;D;D;D;D

Polyphen

0.95

.;.;P;.;.;.

Vest4

0.44

MutPred

0.77

Loss of methylation at R30 (P = 0.035);Loss of methylation at R30 (P = 0.035);Loss of methylation at R30 (P = 0.035);Loss of methylation at R30 (P = 0.035);Loss of methylation at R30 (P = 0.035);Loss of methylation at R30 (P = 0.035);

MVP

0.22

MPC

0.32

ClinPred

0.89

GERP RS

1.2

Varity_R

0.18

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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