rs12445683

Variant names:

• chr16-49491327-C-T
• rs12445683
• NM_001379286.1:c.3850-23G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001379286.1(ZNF423):​c.3850-23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,613,774 control chromosomes in the GnomAD database, including 4,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (453 hom., cov: 32)
  • Exomes 𝑓: 0.020 (3839 hom.)
• Consequence: ZNF423 NM_001379286.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.41
• Publications: 6 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 16-49491327-C-T is Benign according to our data. Variant chr16-49491327-C-T is described in ClinVar as [Benign]. Clinvar id is 1231602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.3850-23G>A		intron_variant	Intron 7 of 7	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7	c.3850-23G>A		intron_variant	Intron 7 of 7	5	NM_001379286.1	ENSP00000455588.3

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4690 AN: 152114 Hom.: 451 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0626 AC: 15733 AN: 251152 AF XY: 0.0514

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.0583

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0204 AC: 29835 AN: 1461542 Hom.: 3839 Cov.: 31 AF XY: 0.0189 AC XY: 13721 AN XY: 727086

African (AFR) AF: 0.00200 AC: 67 AN: 33480

American (AMR) AF: 0.232 AC: 10389 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00539 AC: 141 AN: 26136

East Asian (EAS) AF: 0.330 AC: 13102 AN: 39696

South Asian (SAS) AF: 0.00559 AC: 482 AN: 86256

European-Finnish (FIN) AF: 0.0582 AC: 3089 AN: 53118

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.00112 AC: 1245 AN: 1111984

Other (OTH) AF: 0.0217 AC: 1309 AN: 60388

GnomAD4 genome AF: 0.0308 AC: 4695 AN: 152232 Hom.: 453 Cov.: 32 AF XY: 0.0362 AC XY: 2691 AN XY: 74430

African (AFR) AF: 0.00431 AC: 179 AN: 41550

American (AMR) AF: 0.135 AC: 2069 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.281 AC: 1451 AN: 5164

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4824

European-Finnish (FIN) AF: 0.0617 AC: 654 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00315 AC: 214 AN: 68032

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0133 Hom.: 62

Bravo AF: 0.0391

Asia WGS AF: 0.122 AC: 425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.85
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12445683; hg19: chr16-49525238; COSMIC: COSV52177798;