Genetic Variant ZNF423:p.Thr1286Arg (chr16-49491297-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001379286.1(ZNF423):c.3857C>G(p.Thr1286Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1286K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ZNF423
NM_001379286.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.12

Publications

3 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: Unknown, AD, AR Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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

ZNF423 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF423	NM_001379286.1	MANE Select	c.3857C>G	p.Thr1286Arg	missense	Exon 8 of 8	NP_001366215.1	A0A7P0Q1F0
ZNF423	NM_015069.5		c.3833C>G	p.Thr1278Arg	missense	Exon 8 of 8	NP_055884.2
ZNF423	NM_001271620.2		c.3653C>G	p.Thr1218Arg	missense	Exon 8 of 8	NP_001258549.1	Q2M1K9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF423	ENST00000563137.7	TSL:5 MANE Select	c.3857C>G	p.Thr1286Arg	missense	Exon 8 of 8	ENSP00000455588.3	A0A7P0Q1F0
ZNF423	ENST00000562520.1	TSL:1	c.3653C>G	p.Thr1218Arg	missense	Exon 8 of 8	ENSP00000457664.1	Q2M1K9-2
ZNF423	ENST00000567169.5	TSL:1	c.3482C>G	p.Thr1161Arg	missense	Exon 6 of 6	ENSP00000455061.1	F5H7S1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.085

PhyloP100

9.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.34

Sift

Uncertain

0.011

Sift4G

Uncertain

0.048

Polyphen

0.45

Vest4

0.79

MutPred

0.55

Gain of loop (P = 0.1081)

MVP

0.51

MPC

1.4

ClinPred

0.60

GERP RS

5.3

Varity_R

0.32

gMVP

0.92

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over