rs16947741

Variant names:

• chr16-49637307-C-T
• rs16947741
• NM_001379286.1:c.1869G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379286.1(ZNF423):​c.1869G>A​(p.Pro623Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,614,166 control chromosomes in the GnomAD database, including 890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (86 hom., cov: 33)
  • Exomes 𝑓: 0.029 (804 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.72
• Publications: 7 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=-0.83).
• BP6: Variant 16-49637307-C-T is Benign according to our data. Variant chr16-49637307-C-T is described in ClinVar as Benign. ClinVar VariationId is 260523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.72 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

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.1869G>A	p.Pro623Pro	synonymous	Exon 4 of 8	NP_001366215.1
	ZNF423	NM_015069.5		c.1845G>A	p.Pro615Pro	synonymous	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.1665G>A	p.Pro555Pro	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.1869G>A	p.Pro623Pro	synonymous	Exon 4 of 8	ENSP00000455588.3
	ZNF423	ENST00000562520.1	TSL:1	c.1665G>A	p.Pro555Pro	synonymous	Exon 4 of 8	ENSP00000457664.1
	ZNF423	ENST00000567169.5	TSL:1	c.1494G>A	p.Pro498Pro	synonymous	Exon 2 of 6	ENSP00000455061.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4409 AN: 152190 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.0450

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0393

GnomAD2 exomes AF: 0.0311 AC: 7815 AN: 251348 AF XY: 0.0332

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0567

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.0320

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0294 AC: 43041 AN: 1461858 Hom.: 804 Cov.: 40 AF XY: 0.0308 AC XY: 22375 AN XY: 727236

African (AFR) AF: 0.0214 AC: 716 AN: 33480

American (AMR) AF: 0.0140 AC: 628 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 1509 AN: 26136

East Asian (EAS) AF: 0.00605 AC: 240 AN: 39700

South Asian (SAS) AF: 0.0521 AC: 4492 AN: 86256

European-Finnish (FIN) AF: 0.0341 AC: 1819 AN: 53396

Middle Eastern (MID) AF: 0.0837 AC: 483 AN: 5768

European-Non Finnish (NFE) AF: 0.0281 AC: 31243 AN: 1112004

Other (OTH) AF: 0.0316 AC: 1911 AN: 60394

GnomAD4 genome AF: 0.0289 AC: 4409 AN: 152308 Hom.: 86 Cov.: 33 AF XY: 0.0301 AC XY: 2241 AN XY: 74472

African (AFR) AF: 0.0188 AC: 783 AN: 41584

American (AMR) AF: 0.0185 AC: 283 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5182

South Asian (SAS) AF: 0.0450 AC: 217 AN: 4818

European-Finnish (FIN) AF: 0.0386 AC: 410 AN: 10614

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0326 AC: 2215 AN: 68026

Other (OTH) AF: 0.0394 AC: 83 AN: 2108

Alfa AF: 0.0307 Hom.: 173

Bravo AF: 0.0255

Asia WGS AF: 0.0420 AC: 144 AN: 3478

EpiCase AF: 0.0326

EpiControl AF: 0.0343

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nephronophthisis 14 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.88
DANN	Benign	0.70
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs16947741; hg19: chr16-49671218; COSMIC: COSV52186680;