rs117266679

chr16-49638864-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001379286.1(ZNF423):c.312C>T(p.Asp104=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00241 in 1,604,076 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (21 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.55

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-49638864-G-A is Benign according to our data. Variant chr16-49638864-G-A is described in ClinVar as [Benign]. Clinvar id is 260531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-49638864-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00204 (310/152294) while in subpopulation EAS AF= 0.0182 (94/5176). AF 95% confidence interval is 0.0152. There are 1 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF423	NM_001379286.1	c.312C>T	p.Asp104=	synonymous_variant	4/8	ENST00000563137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF423	ENST00000563137.7	c.312C>T	p.Asp104=	synonymous_variant	4/8	5	NM_001379286.1	P1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00393 AC: 957 AN: 243306 Hom.: 10 AF XY: 0.00423 AC XY: 554 AN XY: 131050

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00196

Gnomad EAS exome AF: 0.0239

Gnomad SAS exome AF: 0.00612

Gnomad FIN exome AF: 0.0000949

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00245 AC: 3559 AN: 1451782 Hom.: 21 Cov.: 35 AF XY: 0.00261 AC XY: 1879 AN XY: 720536

Gnomad4 AFR exome AF: 0.000420

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00220

Gnomad4 EAS exome AF: 0.0149

Gnomad4 SAS exome AF: 0.00591

Gnomad4 FIN exome AF: 0.000283

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00204 AC: 310 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74452

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0182

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00224

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 29, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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ZNF423-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

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

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	13
Dann	Benign	0.67

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: rs117266679; hg19: chr16-49672775;