16-49635815-C-T

Position:

chr16-49635815-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379286.1(ZNF423):c.3361G>A(p.Ala1121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,609,014 control chromosomes in the GnomAD database, including 244 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 7 hom., cov: 33)

Exomes 𝑓: 0.015 ( 237 hom. )

Consequence

ZNF423
NM_001379286.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.624

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=0.0026418269).

BP6

Variant 16-49635815-C-T is Benign according to our data. Variant chr16-49635815-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-49635815-C-T is described in Lovd as [Likely_benign]. Variant chr16-49635815-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1736/152268) while in subpopulation NFE AF= 0.0177 (1204/68008). AF 95% confidence interval is 0.0169. There are 7 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF423	NM_001379286.1 linkuse as main transcript	c.3361G>A	p.Ala1121Thr	missense_variant	4/8	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7 linkuse as main transcript	c.3361G>A	p.Ala1121Thr	missense_variant	4/8	5	NM_001379286.1	ENSP00000455588	P1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1737

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0129

AC:

3089

AN:

239726

Hom.:

AF XY:

0.0134

AC XY:

1755

AN XY:

131014

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00476

Gnomad ASJ exome

AF:

0.00540

Gnomad EAS exome

AF:

0.0000562

Gnomad SAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

AF:

0.0154

AC:

22394

AN:

1456746

Hom.:

237

Cov.:

AF XY:

0.0154

AC XY:

11151

AN XY:

724592

show subpopulations

Gnomad4 AFR exome

AF:

0.00213

Gnomad4 AMR exome

AF:

0.00555

Gnomad4 ASJ exome

AF:

0.00506

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00950

Gnomad4 FIN exome

AF:

0.0263

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0138

GnomAD4 genome

AF:

0.0114

AC:

1736

AN:

152268

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

868

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00274

Gnomad4 AMR

AF:

0.00752

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00913

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.0177

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.00972

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.0206

AC:

177

ExAC

AF:

0.0130

AC:

1561

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephronophthisis 14

Benign:4

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	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.054

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

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.60

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

MetaRNN

Benign

0.0026

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.34

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.38

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

REVEL

Benign

0.014

Sift

Benign

0.96

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

Sift4G

Benign

0.49

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

Polyphen

0.016

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

Vest4

0.010

MPC

0.36

ClinPred

0.00031

GERP RS

1.6

Varity_R

0.014

gMVP

0.12

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