16-49637163-C-T

Position:

• chr16-49637163-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001379286.1(ZNF423):​c.2013G>A​(p.Ala671Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,613,720 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (11 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.702

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 16-49637163-C-T is Benign according to our data. Variant chr16-49637163-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-49637163-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.702 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00207 (315/152308) while in subpopulation NFE AF= 0.00351 (239/68030). AF 95% confidence interval is 0.00315. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.2013G>A	p.Ala671Ala	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.2013G>A	p.Ala671Ala	synonymous_variant	4/8	5	NM_001379286.1	ENSP00000455588.3

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152190 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00200 AC: 500 AN: 250410 Hom.: 3 AF XY: 0.00193 AC XY: 261 AN XY: 135438

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00266 AC: 3889 AN: 1461412 Hom.: 11 Cov.: 37 AF XY: 0.00258 AC XY: 1873 AN XY: 726994

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00389

Gnomad4 NFE exome AF: 0.00310

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152308 Hom.: 1 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74476

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00241 Hom.: 1

Bravo AF: 0.00154

EpiCase AF: 0.00245

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nephronophthisis 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

ZNF423: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.72
DANN	Benign	0.69

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: rs143468235; hg19: chr16-49671074;