rs147898137

Variant names:

• chr16-49635815-C-T
• rs147898137
• NM_001379286.1:c.3361G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-49635815-C-T
• chr16-49635815-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379286.1(ZNF423):​c.3361G>A​(p.Ala1121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,609,014 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1121V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., cov: 33)
  • Exomes 𝑓: 0.015 (237 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.624
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026418269).
• BP6: Variant 16-49635815-C-T is Benign according to our data. Variant chr16-49635815-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1736/152268) while in subpopulation NFE AF = 0.0177 (1204/68008). AF 95% confidence interval is 0.0169. There are 7 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 Unknown,AD,AR gene

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.3361G>A	p.Ala1121Thr	missense	Exon 4 of 8	NP_001366215.1	A0A7P0Q1F0
	ZNF423	NM_015069.5		c.3337G>A	p.Ala1113Thr	missense	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.3157G>A	p.Ala1053Thr	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.3361G>A	p.Ala1121Thr	missense	Exon 4 of 8	ENSP00000455588.3	A0A7P0Q1F0
	ZNF423	ENST00000562520.1	TSL:1	c.3157G>A	p.Ala1053Thr	missense	Exon 4 of 8	ENSP00000457664.1	Q2M1K9-2
	ZNF423	ENST00000567169.5	TSL:1	c.2986G>A	p.Ala996Thr	missense	Exon 2 of 6	ENSP00000455061.1	F5H7S1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1737 AN: 152150 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0129 AC: 3089 AN: 239726 AF XY: 0.0134

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00540

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0154 AC: 22394 AN: 1456746 Hom.: 237 Cov.: 31 AF XY: 0.0154 AC XY: 11151 AN XY: 724592

African (AFR) AF: 0.00213 AC: 71 AN: 33294

American (AMR) AF: 0.00555 AC: 244 AN: 43932

Ashkenazi Jewish (ASJ) AF: 0.00506 AC: 131 AN: 25910

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39638

South Asian (SAS) AF: 0.00950 AC: 816 AN: 85920

European-Finnish (FIN) AF: 0.0263 AC: 1364 AN: 51774

Middle Eastern (MID) AF: 0.00939 AC: 54 AN: 5752

European-Non Finnish (NFE) AF: 0.0170 AC: 18884 AN: 1110322

Other (OTH) AF: 0.0138 AC: 829 AN: 60204

GnomAD4 genome AF: 0.0114 AC: 1736 AN: 152268 Hom.: 7 Cov.: 33 AF XY: 0.0117 AC XY: 868 AN XY: 74464

African (AFR) AF: 0.00274 AC: 114 AN: 41558

American (AMR) AF: 0.00752 AC: 115 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00913 AC: 44 AN: 4820

European-Finnish (FIN) AF: 0.0203 AC: 216 AN: 10628

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0177 AC: 1204 AN: 68008

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0156 Hom.: 12

Bravo AF: 0.00972

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.0206 AC: 177

ExAC AF: 0.0130 AC: 1561

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Nephronophthisis 14 (4)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.77
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.62
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.014
Sift	Benign	0.96	T
Sift4G	Benign	0.49	T
Polyphen		0.016	B
Vest4		0.010
MPC		0.36
ClinPred		0.00031	T
GERP RS		1.6
Varity_R		0.014
gMVP		0.12
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: rs147898137; hg19: chr16-49669726; COSMIC: COSV52189466;