16-49491301-G-A

Position:

• chr16-49491301-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001379286.1(ZNF423):​c.3853C>T​(p.His1285Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 16-49491301-G-A is Pathogenic according to our data. Variant chr16-49491301-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37289.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.3853C>T	p.His1285Tyr	missense_variant	8/8	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7	c.3853C>T	p.His1285Tyr	missense_variant	8/8	5	NM_001379286.1	ENSP00000455588	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Joubert syndrome 19 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 03, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.;D;.;.;.
Eigen	Benign	0.057
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;.;D;.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	M;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.0010	B;.;.;B;.;.;.
Vest4		0.70
MutPred		0.70		Loss of disorder (P = 0.0281);.;.;Loss of disorder (P = 0.0281);.;.;.;
MVP		0.77
MPC		1.4
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.51
gMVP		0.98

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

Other links and lift over

dbSNP: rs1596988259; hg19: chr16-49525212;