rs3803665

Variant names:

• chr16-49638609-A-G
• rs3803665
• NM_001379286.1:c.567T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-49638609-A-G
• chr16-49638609-A-T

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.567T>C​(p.Arg189Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,613,480 control chromosomes in the GnomAD database, including 174,513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (25640 hom., cov: 32)
  • Exomes 𝑓: 0.45 (148873 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.615
• Publications: 21 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=-0.56).
• BP6: Variant 16-49638609-A-G is Benign according to our data. Variant chr16-49638609-A-G is described in ClinVar as Benign. ClinVar VariationId is 260538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.615 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 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.567T>C	p.Arg189Arg	synonymous	Exon 4 of 8	NP_001366215.1	A0A7P0Q1F0
	ZNF423	NM_015069.5		c.543T>C	p.Arg181Arg	synonymous	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.363T>C	p.Arg121Arg	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.567T>C	p.Arg189Arg	synonymous	Exon 4 of 8	ENSP00000455588.3	A0A7P0Q1F0
	ZNF423	ENST00000562520.1	TSL:1	c.363T>C	p.Arg121Arg	synonymous	Exon 4 of 8	ENSP00000457664.1	Q2M1K9-2
	ZNF423	ENST00000567169.5	TSL:1	c.192T>C	p.Arg64Arg	synonymous	Exon 2 of 6	ENSP00000455061.1	F5H7S1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83556 AN: 151906 Hom.: 25580 Cov.: 32

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.478

GnomAD2 exomes AF: 0.472 AC: 118238 AN: 250524 AF XY: 0.466

Gnomad AFR exome AF: 0.857

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.457

Gnomad FIN exome AF: 0.450

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.445 AC: 650415 AN: 1461456 Hom.: 148873 Cov.: 82 AF XY: 0.445 AC XY: 323878 AN XY: 727034

African (AFR) AF: 0.858 AC: 28723 AN: 33480

American (AMR) AF: 0.474 AC: 21188 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9595 AN: 26134

East Asian (EAS) AF: 0.469 AC: 18598 AN: 39692

South Asian (SAS) AF: 0.514 AC: 44326 AN: 86248

European-Finnish (FIN) AF: 0.447 AC: 23771 AN: 53158

Middle Eastern (MID) AF: 0.419 AC: 2414 AN: 5768

European-Non Finnish (NFE) AF: 0.427 AC: 475042 AN: 1111908

Other (OTH) AF: 0.443 AC: 26758 AN: 60378

GnomAD4 genome AF: 0.550 AC: 83685 AN: 152024 Hom.: 25640 Cov.: 32 AF XY: 0.546 AC XY: 40601 AN XY: 74308

African (AFR) AF: 0.846 AC: 35112 AN: 41484

American (AMR) AF: 0.458 AC: 7004 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3468

East Asian (EAS) AF: 0.459 AC: 2366 AN: 5158

South Asian (SAS) AF: 0.506 AC: 2427 AN: 4798

European-Finnish (FIN) AF: 0.442 AC: 4671 AN: 10568

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.431 AC: 29260 AN: 67944

Other (OTH) AF: 0.480 AC: 1014 AN: 2112

Alfa AF: 0.482 Hom.: 18526

Bravo AF: 0.565

Asia WGS AF: 0.483 AC: 1680 AN: 3478

EpiCase AF: 0.423

EpiControl AF: 0.423

ClinVar

ClinVar submissions

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	-0.56
CADD	Benign	0.78
DANN	Benign	0.61
PhyloP100		-0.61
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: rs3803665; hg19: chr16-49672520; COSMIC: COSV52199648;