Variant 19-43872784-C-T 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_001033719.3(ZNF404):c.1430G>A(p.Arg477His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,611,240 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

ZNF404
NM_001033719.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.61

Variant links:

Genes affected

ZNF404 (HGNC:19417): (zinc finger protein 404) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF404 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=0.017765343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF404	NM_001033719.3 link	c.1430G>A	p.Arg477His	missense_variant	3/3	ENST00000587539.2	NP_001028891.2	Q494X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF404	ENST00000587539.2 link	c.1430G>A	p.Arg477His	missense_variant	3/3	5	NM_001033719.3	ENSP00000466051.1		Q494X3

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000810

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000441

AC:

108

AN:

244832

Hom.:

AF XY:

0.000445

AC XY:

AN XY:

132690

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000277

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000743

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.000745

AC:

1087

AN:

1459098

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

516

AN XY:

725642

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000294

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000698

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000916

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.000440

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000810

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000477

Hom.:

Bravo

AF:

0.000450

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.000589

AC:

ExAC

AF:

0.000487

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

Sep 21, 2021

The c.1430G>A (p.R477H) alteration is located in exon 3 (coding exon 3) of the ZNF404 gene. This alteration results from a G to A substitution at nucleotide position 1430, causing the arginine (R) at amino acid position 477 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0055

T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.00040

LIST_S2

Benign

0.22

T;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.51

N;.

PrimateAI

Benign

0.31

REVEL

Benign

0.066

Sift4G

Benign

0.25

T;T

Polyphen

0.99

D;.

Vest4

0.073

MVP

0.17

MPC

0.59

ClinPred

0.12

GERP RS

-2.5

Varity_R

0.026

gMVP

0.029

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