chr16-49636414-G-T

Variant names:

• chr16-49636414-G-T
• rs200585917
• NM_001379286.1:c.2762C>A
• ZNF423 p.Pro921Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001379286.1(ZNF423):c.2762C>A (p.Pro921Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P921L: Uncertain_significance (ClinVar VariationId 37287, 2 stars); 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); it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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>A p.Pro921Gln	missense	Exon 4 of 8	Prot: NP_001366215.1 UniProt:
	ZNF423 NM_015069.5		c.2738C>A p.Pro913Gln	missense	Exon 4 of 8	Prot: NP_055884.2
	ZNF423 NM_001271620.2		c.2558C>A p.Pro853Gln	missense	Exon 4 of 8	Prot: NP_001258549.1 UniProt:

ZNF423 NM_001379286.1

MANE Select

HGVSc / HGVSpc.2762C>Ap.Pro921Gln

Exon rankExon 4 of 8

missense

Prot: NP_001366215.1UniProt: A0A7P0Q1F0

ZNF423 NM_015069.5

HGVSc / HGVSpc.2738C>Ap.Pro913Gln

Exon rankExon 4 of 8

missense

Prot: NP_055884.2

ZNF423 NM_001271620.2

HGVSc / HGVSpc.2558C>Ap.Pro853Gln

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>A p.Pro921Gln	missense	Exon 4 of 8	Prot: ENSP00000455588.3 UniProt:
	ZNF423 ENST00000562520.1	TSL:1	c.2558C>A p.Pro853Gln	missense	Exon 4 of 8	Prot: ENSP00000457664.1 UniProt:
	ZNF423 ENST00000567169.5	TSL:1	c.2387C>A p.Pro796Gln	missense	Exon 2 of 6	Prot: ENSP00000455061.1 UniProt:

ZNF423 ENST00000563137.7

TSL:5MANE Select

HGVSc / HGVSpc.2762C>Ap.Pro921Gln

Exon rankExon 4 of 8

missense

Prot: ENSP00000455588.3UniProt: A0A7P0Q1F0

ZNF423 ENST00000562520.1

TSL:1

HGVSc / HGVSpc.2558C>Ap.Pro853Gln

Exon rankExon 4 of 8

missense

Prot: ENSP00000457664.1UniProt: Q2M1K9-2

ZNF423 ENST00000567169.5

TSL:1

HGVSc / HGVSpc.2387C>Ap.Pro796Gln

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.16
GPN-Star LLR	N/A	-8.2
GPN-Star score	N/A	8.2
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.92	T
Mutation Taster	N/A	10/90	disease causing
MutationAssessor	Uncertain	2.9	M
PhyloP100	Pathogenic	10
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0050	D
Varity_R	N/A	0.30
VESM-3B	Benign	-6.5

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;

COSMIC: COSV52191089;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar