16-49637681-C-A

Variant names:

• chr16-49637681-C-A
• NM_001379286.1:c.1495G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001379286.1(ZNF423):​c.1495G>T​(p.Asp499Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.1495G>T	p.Asp499Tyr	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	c.1495G>T	p.Asp499Tyr	missense_variant	Exon 4 of 8	5	NM_001379286.1	ENSP00000455588.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;.;D;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;D;.;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.;L;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0060	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.88
MutPred		0.67		Gain of catalytic residue at D491 (P = 0.0891);.;.;Gain of catalytic residue at D491 (P = 0.0891);.;.;.;
MVP		0.26
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.52
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-49671592; COSMIC: COSV52199979;