rs200494811

Variant names:

• chr16-49635922-T-C
• rs200494811
• NM_001379286.1:c.3254A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001379286.1(ZNF423):​c.3254A>G​(p.Gln1085Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000629 in 1,587,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.07
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14473999).

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.3254A>G	p.Gln1085Arg	missense	Exon 4 of 8	NP_001366215.1	A0A7P0Q1F0
	ZNF423	NM_015069.5		c.3230A>G	p.Gln1077Arg	missense	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.3050A>G	p.Gln1017Arg	missense	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.3254A>G	p.Gln1085Arg	missense	Exon 4 of 8	ENSP00000455588.3	A0A7P0Q1F0
	ZNF423	ENST00000562520.1	TSL:1	c.3050A>G	p.Gln1017Arg	missense	Exon 4 of 8	ENSP00000457664.1	Q2M1K9-2
	ZNF423	ENST00000567169.5	TSL:1	c.2879A>G	p.Gln960Arg	missense	Exon 2 of 6	ENSP00000455061.1	F5H7S1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000224 AC: 51 AN: 227498 AF XY: 0.000180

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.000447

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.000672 AC: 964 AN: 1435192 Hom.: 0 Cov.: 31 AF XY: 0.000646 AC XY: 459 AN XY: 710678

African (AFR) AF: 0.0000606 AC: 2 AN: 32978

American (AMR) AF: 0.0000235 AC: 1 AN: 42564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24170

East Asian (EAS) AF: 0.00 AC: 0 AN: 39424

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81134

European-Finnish (FIN) AF: 0.0000582 AC: 3 AN: 51582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.000836 AC: 918 AN: 1098446

Other (OTH) AF: 0.000658 AC: 39 AN: 59264

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74346

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000331 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000198 AC: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.17
Sift	Uncertain	0.017	D
Sift4G	Benign	0.12	T
Polyphen		0.76	P
Vest4		0.37
MVP		0.043
MPC		0.73
ClinPred		0.090	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.33
Mutation Taster		=68/32	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: rs200494811; hg19: chr16-49669833;