Variant chr19-58477235-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017908.4(ZNF446):c.17G>A(p.Gly6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,576,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ZNF446
NM_017908.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0820

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08031216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4 link	c.17G>A	p.Gly6Asp	missense_variant	2/7	ENST00000594369.6	NP_060378.1	Q9NWS9-1Q9UFF2
ZNF446	NM_001304453.1 link	c.17G>A	p.Gly6Asp	missense_variant	1/6		NP_001291382.1	Q8NDK2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF446	ENST00000594369.6 link	c.17G>A	p.Gly6Asp	missense_variant	2/7	1	NM_017908.4	ENSP00000472802.1		Q9NWS9-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152014

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

228216

Hom.:

AF XY:

0.0000323

AC XY:

AN XY:

123776

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:

0.0000737

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000442

AC:

AN:

1424762

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

704744

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:

0.000157

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000431

Gnomad4 OTH exome

AF:

0.0000342

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74248

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000825

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

Aug 04, 2023

The c.17G>A (p.G6D) alteration is located in exon 2 (coding exon 1) of the ZNF446 gene. This alteration results from a G to A substitution at nucleotide position 17, causing the glycine (G) at amino acid position 6 to be replaced by an aspartic acid (D). 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

0.29

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.019

T;T;T;.;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.60

T;T;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.080

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

.;.;M;.;.;M

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.1

.;.;.;.;N;.

REVEL

Benign

0.032

Sift

Benign

0.047

.;.;.;.;D;.

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

0.0010

.;.;B;.;.;.

Vest4

0.34

MutPred

0.22

Loss of glycosylation at S3 (P = 0.0718);Loss of glycosylation at S3 (P = 0.0718);Loss of glycosylation at S3 (P = 0.0718);Loss of glycosylation at S3 (P = 0.0718);Loss of glycosylation at S3 (P = 0.0718);Loss of glycosylation at S3 (P = 0.0718);

MVP

0.11

MPC

0.086

ClinPred

0.062

GERP RS

1.3

Varity_R

0.074

gMVP

0.52

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