chr16-49636641-G-A

Variant names:

• chr16-49636641-G-A
• rs77996576
• NM_001379286.1:c.2535C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001379286.1(ZNF423):​c.2535C>T​(p.Thr845Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,614,026 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T845T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (33 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.996
• Publications: 1 publications found

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]

ZNF423 Gene-Disease associations (from GenCC):

• nephronophthisis 14

  Inheritance: AD, Unknown, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-49636641-G-A is Benign according to our data. Variant chr16-49636641-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.996 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1784/152256) while in subpopulation AFR AF = 0.0407 (1691/41544). AF 95% confidence interval is 0.0391. There are 36 homozygotes in GnomAd4. There are 860 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379286.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	NM_001379286.1	MANE Select	c.2535C>T	p.Thr845Thr	synonymous	Exon 4 of 8	NP_001366215.1
	ZNF423	NM_015069.5		c.2511C>T	p.Thr837Thr	synonymous	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.2331C>T	p.Thr777Thr	synonymous	Exon 4 of 8	NP_001258549.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	ENST00000563137.7	TSL:5 MANE Select	c.2535C>T	p.Thr845Thr	synonymous	Exon 4 of 8	ENSP00000455588.3
	ZNF423	ENST00000562520.1	TSL:1	c.2331C>T	p.Thr777Thr	synonymous	Exon 4 of 8	ENSP00000457664.1
	ZNF423	ENST00000567169.5	TSL:1	c.2160C>T	p.Thr720Thr	synonymous	Exon 2 of 6	ENSP00000455061.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1787 AN: 152138 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00325 AC: 816 AN: 250852 AF XY: 0.00238

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00125 AC: 1823 AN: 1461770 Hom.: 33 Cov.: 37 AF XY: 0.00109 AC XY: 794 AN XY: 727166

African (AFR) AF: 0.0403 AC: 1348 AN: 33480

American (AMR) AF: 0.00242 AC: 108 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000148 AC: 165 AN: 1111984

Other (OTH) AF: 0.00311 AC: 188 AN: 60390

GnomAD4 genome AF: 0.0117 AC: 1784 AN: 152256 Hom.: 36 Cov.: 33 AF XY: 0.0116 AC XY: 860 AN XY: 74444

African (AFR) AF: 0.0407 AC: 1691 AN: 41544

American (AMR) AF: 0.00373 AC: 57 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.00550 Hom.: 14

Bravo AF: 0.0137

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 14 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.025
DANN	Benign	0.32
PhyloP100		-1.0
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs77996576; hg19: chr16-49670552;