chr16-49636414-G-A

Variant names:

• chr16-49636414-G-A
• rs200585917
• NM_001379286.1:c.2762C>T
• ZNF423 p.Pro921Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NM_001379286.1(ZNF423):c.2762C>T (p.Pro921Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The gene ZNF423 is a known oncogene (CancerMine: 2 oncogene citations). The variant allele was found at a cumulative frequency of 0.000155 (AC=250) in the gnomAD database across 1,613,276 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000502. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.99). Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P921= (synonymous): Likely_benign (ClinVar VariationId 1370676, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Nephronophthisis 14 (nphp14).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 9.99
• Publications: 8 publications found

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: AR, AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• ciliopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001379286.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZNF423 NM_001379286.1	MANE Select	c.2762C>T p.Pro921Leu	missense	Exon 4 of 8	Prot: NP_001366215.1 UniProt:
	ZNF423 NM_015069.5		c.2738C>T p.Pro913Leu	missense	Exon 4 of 8	Prot: NP_055884.2
	ZNF423 NM_001271620.2		c.2558C>T p.Pro853Leu	missense	Exon 4 of 8	Prot: NP_001258549.1 UniProt:

ZNF423 NM_001379286.1

MANE Select

HGVSc / HGVSpc.2762C>Tp.Pro921Leu

Exon rankExon 4 of 8

missense

Prot: NP_001366215.1UniProt: A0A7P0Q1F0

ZNF423 NM_015069.5

HGVSc / HGVSpc.2738C>Tp.Pro913Leu

Exon rankExon 4 of 8

missense

Prot: NP_055884.2

ZNF423 NM_001271620.2

HGVSc / HGVSpc.2558C>Tp.Pro853Leu

Exon rankExon 4 of 8

missense

Prot: NP_001258549.1UniProt: B3KNG7Q2M1K9-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZNF423 ENST00000563137.7	TSL:5MANE Select	c.2762C>T p.Pro921Leu	missense	Exon 4 of 8	Prot: ENSP00000455588.3 UniProt:
	ZNF423 ENST00000562520.1	TSL:1	c.2558C>T p.Pro853Leu	missense	Exon 4 of 8	Prot: ENSP00000457664.1 UniProt:
	ZNF423 ENST00000567169.5	TSL:1	c.2387C>T p.Pro796Leu	missense	Exon 2 of 6	Prot: ENSP00000455061.1 UniProt:

ZNF423 ENST00000563137.7

TSL:5MANE Select

HGVSc / HGVSpc.2762C>Tp.Pro921Leu

Exon rankExon 4 of 8

missense

Prot: ENSP00000455588.3UniProt: A0A7P0Q1F0

ZNF423 ENST00000562520.1

TSL:1

HGVSc / HGVSpc.2558C>Tp.Pro853Leu

Exon rankExon 4 of 8

missense

Prot: ENSP00000457664.1UniProt: Q2M1K9-2

ZNF423 ENST00000567169.5

TSL:1

HGVSc / HGVSpc.2387C>Tp.Pro796Leu

Exon rankExon 2 of 6

missense

Prot: ENSP00000455061.1UniProt: F5H7S1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000223	AC:34	Hom:0	AN:152146	Cov:33
GnomAD2 exomes	AF: 0.000175	AC:44	Hom:	AN:250946	Cov:
GnomAD4 exome	AF: 0.000148	AC:216	Hom:0	AN:1461012	Cov:32
GnomAD4 genome	AF: 0.000223	AC:34	Hom:0	AN:152264	Cov:33
TOPMed (Bravo)	AF: 0.000276	AC:73	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000261	AC:74	Hom:0	AN:283036	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000148	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000154	AC:2	Hom:	AN:12992	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00120	AC:2	Hom:	AN:1706	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000240	AC:3	Hom:0	AN:122648	Cov:
Turkish Variome	AF: 0.00109	AC:7	Hom:0	AN:6422	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	10998	0.000285 *	5	17550
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.000208	6	28844
Epi25(Epilepsy)	0.000358	15	41958	0.000284	19	66888
SCHEMA(Schizophrenia)	0.000315	38	120556	0.000550	104	188944

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	2	-	Nephronophthisis 14 (3)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.36
GPN-Star LLR	N/A	-8.7
GPN-Star score	N/A	8.7
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	1/99	disease causing
MutationAssessor	Uncertain	2.9	M
PhyloP100	Pathogenic	10
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.014	D
Varity_R	N/A	0.26
VESM-3B	Benign	-6.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200585917;

hg19: chr16-49670325;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar