rs34214571

Positions:

chr16-49637266-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001379286.1(ZNF423):c.1910A>G(p.Asn637Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0293 in 1,614,178 control chromosomes in the GnomAD database, including 883 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N637H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.028 ( 84 hom., cov: 33)

Exomes 𝑓: 0.029 ( 799 hom. )

Consequence

ZNF423
NM_001379286.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.91

Variant links:

Genes affected

ZNF423 (HGNC:16762): (zinc finger protein 423) The protein encoded by this gene is a nuclear protein that belongs to the family of Kruppel-like C2H2 zinc finger proteins. It functions as a DNA-binding transcription factor by using distinct zinc fingers in different signaling pathways. Thus, it is thought that this gene may have multiple roles in signal transduction during development. Mutations in this gene are associated with nephronophthisis-14 and Joubert syndrome-19. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2012]

ZNF423 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZNF423. . Gene score misZ 2.4902 (greater than the threshold 3.09). Trascript score misZ 4.2773 (greater than threshold 3.09). GenCC has associacion of gene with nephronophthisis 14, Joubert syndrome 17, nephronophthisis 2, Joubert syndrome with oculorenal defect, nephronophthisis.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020326376).

BP6

Variant 16-49637266-T-C is Benign according to our data. Variant chr16-49637266-T-C is described in ClinVar as [Benign]. Clinvar id is 260524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-49637266-T-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF423	NM_001379286.1 linkuse as main transcript	c.1910A>G	p.Asn637Ser	missense_variant	4/8	ENST00000563137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF423	ENST00000563137.7 linkuse as main transcript	c.1910A>G	p.Asn637Ser	missense_variant	4/8	5	NM_001379286.1	P1

Frequencies

GnomAD3 genomes

AF:

0.0283

AC:

4309

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0165

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0185

Gnomad ASJ

AF:

0.0611

Gnomad EAS

AF:

0.0121

Gnomad SAS

AF:

0.0446

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0325

Gnomad OTH

AF:

0.0392

GnomAD3 exomes

AF:

0.0309

AC:

7768

AN:

251424

Hom.:

162

AF XY:

0.0331

AC XY:

4502

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.0136

Gnomad ASJ exome

AF:

0.0566

Gnomad EAS exome

AF:

0.0105

Gnomad SAS exome

AF:

0.0526

Gnomad FIN exome

AF:

0.0355

Gnomad NFE exome

AF:

0.0320

Gnomad OTH exome

AF:

0.0391

GnomAD4 exome

AF:

0.0294

AC:

42939

AN:

1461870

Hom.:

799

Cov.:

AF XY:

0.0307

AC XY:

22326

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0192

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.0577

Gnomad4 EAS exome

AF:

0.00605

Gnomad4 SAS exome

AF:

0.0521

Gnomad4 FIN exome

AF:

0.0340

Gnomad4 NFE exome

AF:

0.0281

Gnomad4 OTH exome

AF:

0.0315

GnomAD4 genome

AF:

0.0283

AC:

4306

AN:

152308

Hom.:

Cov.:

AF XY:

0.0294

AC XY:

2190

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0165

Gnomad4 AMR

AF:

0.0185

Gnomad4 ASJ

AF:

0.0611

Gnomad4 EAS

AF:

0.0120

Gnomad4 SAS

AF:

0.0446

Gnomad4 FIN

AF:

0.0386

Gnomad4 NFE

AF:

0.0325

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0321

Hom.:

101

Bravo

AF:

0.0247

TwinsUK

AF:

0.0278

AC:

103

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.0187

AC:

ESP6500EA

AF:

0.0320

AC:

275

ExAC

AF:

0.0317

AC:

3852

Asia WGS

AF:

0.0410

AC:

143

AN:

3478

EpiCase

AF:

0.0326

EpiControl

AF:

0.0343

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephronophthisis 14

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.078

T;.;.;T;.;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.047

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

.;.;.;T;.;T;T

MetaRNN

Benign

0.0020

T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

N;.;.;N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.59

N;N;N;N;N;N;N

REVEL

Benign

0.094

Sift

Benign

0.73

T;T;T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;T;T

Polyphen

0.0020

B;.;.;B;.;.;.

Vest4

0.20

MPC

0.30

ClinPred

0.012

GERP RS

4.8

Varity_R

0.084

gMVP

0.11

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