rs75294107

Positions:

• chr16-49637190-G-A
• chr16-49637190-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001379286.1(ZNF423):​c.1986C>T​(p.His662=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,613,938 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (58 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.63

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-49637190-G-A is Benign according to our data. Variant chr16-49637190-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 197816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-49637190-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00448 (682/152362) while in subpopulation NFE AF= 0.00757 (515/68034). AF 95% confidence interval is 0.00703. There are 3 homozygotes in gnomad4. There are 277 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.1986C>T	p.His662=	synonymous_variant	4/8	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7	c.1986C>T	p.His662=	synonymous_variant	4/8	5	NM_001379286.1	ENSP00000455588	P1

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 682 AN: 152244 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00757

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00501 AC: 1258 AN: 250870 Hom.: 7 AF XY: 0.00492 AC XY: 667 AN XY: 135640

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.0239

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00782

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00736 AC: 10753 AN: 1461576 Hom.: 58 Cov.: 38 AF XY: 0.00707 AC XY: 5138 AN XY: 727074

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0214

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.00209

Gnomad4 NFE exome AF: 0.00856

Gnomad4 OTH exome AF: 0.00697

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152362 Hom.: 3 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74510

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00757

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00811 Hom.: 7

Bravo AF: 0.00450

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00699

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -

Nephronophthisis 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ZNF423: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.9
DANN	Benign	0.66

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: rs75294107; hg19: chr16-49671101;