16-49491279-T-G

Position:

• chr16-49491279-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_001379286.1(ZNF423):​c.3875A>C​(p.Gln1292Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,614,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1292Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.30

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ZNF423
• BP4: Computational evidence support a benign effect (MetaRNN=0.008133829).
• BP6: Variant 16-49491279-T-G is Benign according to our data. Variant chr16-49491279-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 767050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00194 (296/152328) while in subpopulation AFR AF= 0.0069 (287/41572). AF 95% confidence interval is 0.00625. There are 1 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF423	NM_001379286.1	c.3875A>C	p.Gln1292Pro	missense_variant	8/8	ENST00000563137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF423	ENST00000563137.7	c.3875A>C	p.Gln1292Pro	missense_variant	8/8	5	NM_001379286.1	P1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 296 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00692

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000489 AC: 123 AN: 251404 Hom.: 2 AF XY: 0.000258 AC XY: 35 AN XY: 135872

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000189 AC: 277 AN: 1461780 Hom.: 1 Cov.: 30 AF XY: 0.000166 AC XY: 121 AN XY: 727192

Gnomad4 AFR exome AF: 0.00693

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74478

Gnomad4 AFR AF: 0.00690

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000437 Hom.: 0

Bravo AF: 0.00216

ESP6500AA AF: 0.00750 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

ZNF423: BS2 -

ZNF423-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T;.;.;T;.;.;.
Eigen	Benign	0.015
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0081	T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.34	B;.;.;B;.;.;.
Vest4		0.65
MVP		0.40
MPC		1.5
ClinPred		0.068	T
GERP RS		5.3
Varity_R		0.43
gMVP		0.78

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: rs150302551; hg19: chr16-49525190;