rs34214571

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 13/21 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

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 14
Inheritance: AD, Unknown, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ZNF423 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 260524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ZNF423	NM_001379286.1 link	c.1910A>G	p.Asn637Ser	missense_variant	Exon 4 of 8	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7 link	c.1910A>G	p.Asn637Ser	missense_variant	Exon 4 of 8	5	NM_001379286.1	ENSP00000455588.3

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

GnomAD2 exomes

AF:

0.0309

AC:

7768

AN:

251424

AF XY:

0.0331

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 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

African (AFR)

AF:

0.0192

AC:

644

AN:

33480

American (AMR)

AF:

0.0139

AC:

622

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

1507

AN:

26136

East Asian (EAS)

AF:

0.00605

AC:

240

AN:

39700

South Asian (SAS)

AF:

0.0521

AC:

4493

AN:

86258

European-Finnish (FIN)

AF:

0.0340

AC:

1818

AN:

53400

Middle Eastern (MID)

AF:

0.0832

AC:

480

AN:

5768

European-Non Finnish (NFE)

AF:

0.0281

AC:

31235

AN:

1112008

Other (OTH)

AF:

0.0315

AC:

1900

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

2908

5815

8723

11630

14538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1126

2252

3378

4504

5630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0283

AC:

4306

AN:

152308

Hom.:

Cov.:

AF XY:

0.0294

AC XY:

2190

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0165

AC:

684

AN:

41576

American (AMR)

AF:

0.0185

AC:

283

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0611

AC:

212

AN:

3470

East Asian (EAS)

AF:

0.0120

AC:

AN:

5176

South Asian (SAS)

AF:

0.0446

AC:

215

AN:

4820

European-Finnish (FIN)

AF:

0.0386

AC:

410

AN:

10626

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0325

AC:

2213

AN:

68016

Other (OTH)

AF:

0.0393

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

214

429

643

858

1072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0306

Hom.:

236

Bravo

AF:

0.0247

TwinsUK

AF:

0.0278

AC:

103

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

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nephronophthisis 14

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.078

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

Eigen

Benign

-0.15

Eigen_PC

Benign

0.047

LIST_S2

Benign

0.0

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

MetaRNN

Benign

0.0020

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

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

PhyloP100

5.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.59

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

Sift

Benign

0.73

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

Sift4G

Benign

0.28

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

Vest4

0.20

ClinPred

0.012

GERP RS

4.8

Varity_R

0.084

gMVP

0.11

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over