Variant chr19-58477256-T-C 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.38T>C(p.Met13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,601,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ZNF446
NM_017908.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.205

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=0.05428046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4 linkuse as main transcript	c.38T>C	p.Met13Thr	missense_variant	2/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1 linkuse as main transcript	c.38T>C	p.Met13Thr	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.38T>C	p.Met13Thr	missense_variant	2/7	1	NM_017908.4	ENSP00000472802	P1	Q9NWS9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

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:

0.0000123

AC:

AN:

244488

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1449104

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

719240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000304

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.06e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000824

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

Jun 03, 2024

The c.38T>C (p.M13T) alteration is located in exon 2 (coding exon 1) of the ZNF446 gene. This alteration results from a T to C substitution at nucleotide position 38, causing the methionine (M) at amino acid position 13 to be replaced by a threonine (T). 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

0.24

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.8

DANN

Benign

0.79

DEOGEN2

Benign

0.013

T;T;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.41

T;T;T;T;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.054

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.14

.;.;N;.;.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.42

.;.;.;.;N;.

REVEL

Benign

0.018

Sift

Benign

0.34

.;.;.;.;T;.

Sift4G

Benign

0.14

T;T;T;T;T;T

Polyphen

0.0010

.;.;B;.;.;.

Vest4

0.19

MutPred

0.19

Gain of phosphorylation at M13 (P = 0.0129);Gain of phosphorylation at M13 (P = 0.0129);Gain of phosphorylation at M13 (P = 0.0129);Gain of phosphorylation at M13 (P = 0.0129);Gain of phosphorylation at M13 (P = 0.0129);Gain of phosphorylation at M13 (P = 0.0129);

MVP

0.040

MPC

0.074

ClinPred

0.050

GERP RS

-1.5

Varity_R

0.038

gMVP

0.18

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