rs111229124

chr16-49636012-G-Achr16-49636012-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379286.1(ZNF423):c.3164C>T(p.Ala1055Val) variant causes a missense change. The variant allele was found at a frequency of 0.00852 in 1,606,776 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1055E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (75 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.62

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ZNF423
• BP4: Computational evidence support a benign effect (MetaRNN=0.005976796).
• BP6: Variant 16-49636012-G-A is Benign according to our data. Variant chr16-49636012-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00611 (930/152304) while in subpopulation NFE AF= 0.0102 (695/68014). AF 95% confidence interval is 0.00959. There are 6 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF423	NM_001379286.1	c.3164C>T	p.Ala1055Val	missense_variant	4/8	ENST00000563137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF423	ENST00000563137.7	c.3164C>T	p.Ala1055Val	missense_variant	4/8	5	NM_001379286.1	P1

Frequencies

GnomAD3 genomes AF: 0.00611 AC: 930 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00581 AC: 1437 AN: 247334 Hom.: 10 AF XY: 0.00558 AC XY: 747 AN XY: 133808

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00421

Gnomad ASJ exome AF: 0.000823

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00207

Gnomad FIN exome AF: 0.00257

Gnomad NFE exome AF: 0.00985

Gnomad OTH exome AF: 0.00729

GnomAD4 exome AF: 0.00877 AC: 12754 AN: 1454472 Hom.: 75 Cov.: 32 AF XY: 0.00855 AC XY: 6176 AN XY: 722198

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00453

Gnomad4 ASJ exome AF: 0.00116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00698

GnomAD4 genome AF: 0.00611 AC: 930 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00563 AC XY: 419 AN XY: 74472

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00786 Hom.: 5

Bravo AF: 0.00590

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00583 AC: 708

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ZNF423: BS2 -

Nephronophthisis 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.087	T;.;.;T;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;.;.;N;.;.;.
MutationTaster	Benign	0.88	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
Sift	Benign	0.038	D;D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D
Polyphen		0.0040	B;.;.;B;.;.;.
Vest4		0.13
MVP		0.043
MPC		0.37
ClinPred		0.018	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.22

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: rs111229124; hg19: chr16-49669923; COSMIC: COSV52203203;