rs117592972

chr16-49635996-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001379286.1(ZNF423):c.3180G>A(p.Ala1060=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000715 in 1,602,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.88

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-49635996-C-T is Benign according to our data. Variant chr16-49635996-C-T is described in ClinVar as [Benign]. Clinvar id is 473061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-49635996-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000584 (89/152302) while in subpopulation EAS AF= 0.012 (62/5174). AF 95% confidence interval is 0.00959. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF423	NM_001379286.1	c.3180G>A	p.Ala1060=	synonymous_variant	4/8	ENST00000563137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF423	ENST00000563137.7	c.3180G>A	p.Ala1060=	synonymous_variant	4/8	5	NM_001379286.1	P1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00114 AC: 276 AN: 242938 Hom.: 0 AF XY: 0.00101 AC XY: 132 AN XY: 131250

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.000384

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000228

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000729 AC: 1057 AN: 1449778 Hom.: 1 Cov.: 31 AF XY: 0.000676 AC XY: 486 AN XY: 719248

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000677

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.00952

Gnomad4 SAS exome AF: 0.000248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000557

Gnomad4 OTH exome AF: 0.000551

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74468

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0120

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000740

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

ZNF423-related disorder 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.041
Dann	Benign	0.39

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: rs117592972; hg19: chr16-49669907; COSMIC: COSV52200950;