Genetic Variant ZNF442:p.Arg583His (chr19-12349837-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_030824.3(ZNF442):c.1748G>A(p.Arg583His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,608,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ZNF442
NM_030824.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.76

Variant links:

Genes affected

ZNF442 (HGNC:20877): (zinc finger protein 442) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF442 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=0.05427769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF442	NM_030824.3 link	c.1748G>A	p.Arg583His	missense_variant	Exon 6 of 6	ENST00000242804.9	NP_110451.1	Q9H7R0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF442	ENST00000242804.9 link	c.1748G>A	p.Arg583His	missense_variant	Exon 6 of 6	2	NM_030824.3	ENSP00000242804.4	Q9H7R0-1
ZNF442	ENST00000545749.2 link	c.1748G>A	p.Arg583His	missense_variant	Exon 4 of 4	5		ENSP00000440162.2	Q9H7R0-1
ZNF442	ENST00000438182.5 link	c.1541G>A	p.Arg514His	missense_variant	Exon 3 of 3	2		ENSP00000388634.1	Q9H7R0-2

Frequencies

GnomAD3 genomes

AF:

0.0000202

AC:

AN:

148324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000747

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251248

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1459910

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000202

AC:

AN:

148324

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

72372

show subpopulations

Gnomad4 AFR

AF:

0.0000747

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000189

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

May 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1748G>A (p.R583H) alteration is located in exon 6 (coding exon 4) of the ZNF442 gene. This alteration results from a G to A substitution at nucleotide position 1748, causing the arginine (R) at amino acid position 583 to be replaced by a histidine (H). 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

0.19

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.8

DANN

Benign

0.75

DEOGEN2

Benign

0.0018

T;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.000010

LIST_S2

Benign

0.11

.;T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

L;.;L

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.050

N;N;.

REVEL

Benign

0.011

Sift

Benign

0.55

T;T;.

Sift4G

Benign

0.66

T;T;T

Polyphen

0.036

B;.;B

Vest4

0.060

MVP

0.15

MPC

0.074

ClinPred

0.023

GERP RS

-1.6

Varity_R

0.018

gMVP

0.028

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