NM_001379286.1:c.1569T>C

Variant names:

• chr16-49637607-A-G
• rs13336762
• NM_001379286.1:c.1569T>C

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.1569T>C​(p.Asn523Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 1,613,952 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (611 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (563 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.724
• Publications: 4 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: Unknown, AD, AR Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Joubert syndrome with oculorenal defect

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 16-49637607-A-G is Benign according to our data. Variant chr16-49637607-A-G is described in ClinVar as Benign. ClinVar VariationId is 260522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.724 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	NM_001379286.1	MANE Select	c.1569T>C	p.Asn523Asn	synonymous	Exon 4 of 8	NP_001366215.1	A0A7P0Q1F0
	ZNF423	NM_015069.5		c.1545T>C	p.Asn515Asn	synonymous	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.1365T>C	p.Asn455Asn	synonymous	Exon 4 of 8	NP_001258549.1	Q2M1K9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	ENST00000563137.7	TSL:5 MANE Select	c.1569T>C	p.Asn523Asn	synonymous	Exon 4 of 8	ENSP00000455588.3	A0A7P0Q1F0
	ZNF423	ENST00000562520.1	TSL:1	c.1365T>C	p.Asn455Asn	synonymous	Exon 4 of 8	ENSP00000457664.1	Q2M1K9-2
	ZNF423	ENST00000567169.5	TSL:1	c.1194T>C	p.Asn398Asn	synonymous	Exon 2 of 6	ENSP00000455061.1	F5H7S1

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7397 AN: 152074 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0132 AC: 3319 AN: 251182 AF XY: 0.00976

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.00945

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000589

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00525 AC: 7669 AN: 1461760 Hom.: 563 Cov.: 41 AF XY: 0.00461 AC XY: 3349 AN XY: 727152

African (AFR) AF: 0.174 AC: 5836 AN: 33480

American (AMR) AF: 0.0110 AC: 490 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00532 AC: 139 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5768

European-Non Finnish (NFE) AF: 0.000326 AC: 363 AN: 1112008

Other (OTH) AF: 0.0121 AC: 732 AN: 60396

GnomAD4 genome AF: 0.0486 AC: 7401 AN: 152192 Hom.: 611 Cov.: 32 AF XY: 0.0458 AC XY: 3407 AN XY: 74420

African (AFR) AF: 0.167 AC: 6936 AN: 41492

American (AMR) AF: 0.0213 AC: 325 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 17 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68018

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0193 Hom.: 623

Bravo AF: 0.0559

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.033
DANN	Benign	0.28
PhyloP100		-0.72
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: rs13336762; hg19: chr16-49671518; COSMIC: COSV52183590;