rs111229124

Positions:

Variant summary

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

The NM_001379286.1(ZNF423):c.3164C>T(p.Ala1055Val) variant causes a missense change. The variant allele was found at a frequency of 0.00852 in 1,606,776 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1055A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0061 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0088 ( 75 hom. )

Consequence

ZNF423
NM_001379286.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.62

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=0.005976796).

BP6

Variant 16-49636012-G-A is Benign according to our data. Variant chr16-49636012-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00611 (930/152304) while in subpopulation NFE AF= 0.0102 (695/68014). AF 95% confidence interval is 0.00959. There are 6 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF423	NM_001379286.1 linkuse as main transcript	c.3164C>T	p.Ala1055Val	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.3164C>T	p.Ala1055Val	missense_variant	4/8	5	NM_001379286.1	ENSP00000455588	P1

Frequencies

GnomAD3 genomes

AF:

0.00611

AC:

930

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00581

AC:

1437

AN:

247334

Hom.:

AF XY:

0.00558

AC XY:

747

AN XY:

133808

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00421

Gnomad ASJ exome

AF:

0.000823

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00207

Gnomad FIN exome

AF:

0.00257

Gnomad NFE exome

AF:

0.00985

Gnomad OTH exome

AF:

0.00729

GnomAD4 exome

AF:

0.00877

AC:

12754

AN:

1454472

Hom.:

Cov.:

AF XY:

0.00855

AC XY:

6176

AN XY:

722198

show subpopulations

Gnomad4 AFR exome

AF:

0.00183

Gnomad4 AMR exome

AF:

0.00453

Gnomad4 ASJ exome

AF:

0.00116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00189

Gnomad4 FIN exome

AF:

0.00316

Gnomad4 NFE exome

AF:

0.0106

Gnomad4 OTH exome

AF:

0.00698

GnomAD4 genome

AF:

0.00611

AC:

930

AN:

152304

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00204

Gnomad4 AMR

AF:

0.00653

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00786

Hom.:

Bravo

AF:

0.00590

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00953

AC:

ExAC

AF:

0.00583

AC:

708

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ZNF423: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 01, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nephronophthisis 14

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

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

Eigen

Benign

-0.14

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

.;.;.;D;.;D;D

MetaRNN

Benign

0.0060

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

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

MutationTaster

Benign

0.88

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

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.044

Sift

Benign

0.038

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

Sift4G

Uncertain

0.012

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

Polyphen

0.0040

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

Vest4

0.13

MVP

0.043

MPC

0.37

ClinPred

0.018

GERP RS

5.1

Varity_R

0.13

gMVP

0.22

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