Variant chr19-58477387-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000594369.6(ZNF446):c.169C>G(p.Pro57Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZNF446
ENST00000594369.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4 linkuse as main transcript	c.169C>G	p.Pro57Ala	missense_variant	2/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1 linkuse as main transcript	c.169C>G	p.Pro57Ala	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.169C>G	p.Pro57Ala	missense_variant	2/7	1	NM_017908.4	ENSP00000472802	P1	Q9NWS9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 13, 2023

The c.169C>G (p.P57A) alteration is located in exon 2 (coding exon 1) of the ZNF446 gene. This alteration results from a C to G substitution at nucleotide position 169, causing the proline (P) at amino acid position 57 to be replaced by an alanine (A). 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

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;T;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

3.7

.;.;H;.;.;H

MutationTaster

Benign

0.71

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.8

.;.;.;.;D;.

REVEL

Benign

0.27

Sift

Pathogenic

0.0

.;.;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.53

MutPred

0.92

Loss of catalytic residue at P57 (P = 0.023);Loss of catalytic residue at P57 (P = 0.023);Loss of catalytic residue at P57 (P = 0.023);Loss of catalytic residue at P57 (P = 0.023);Loss of catalytic residue at P57 (P = 0.023);Loss of catalytic residue at P57 (P = 0.023);

MVP

0.17

MPC

0.39

ClinPred

0.97

GERP RS

4.5

Varity_R

0.55

gMVP

0.41

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over