rs117266679

Variant names:

• chr16-49638864-G-A
• rs117266679
• ENST00000567169.5:c.-64C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001330533.2(ZNF423):​c.-64C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00241 in 1,604,076 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (21 hom.)
• Consequence: ZNF423 NM_001330533.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.55
• Publications: 6 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-49638864-G-A is Benign according to our data. Variant chr16-49638864-G-A is described in ClinVar as Benign. ClinVar VariationId is 260531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00204 (310/152294) while in subpopulation EAS AF = 0.0182 (94/5176). AF 95% confidence interval is 0.0152. There are 1 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330533.2. 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.312C>T	p.Asp104Asp	synonymous	Exon 4 of 8	NP_001366215.1	A0A7P0Q1F0
	ZNF423	NM_001330533.2		c.-64C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001317462.1	F5H7S1
	ZNF423	NM_015069.5		c.288C>T	p.Asp96Asp	synonymous	Exon 4 of 8	NP_055884.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	ENST00000567169.5	TSL:1	c.-64C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000455061.1	F5H7S1
	ZNF423	ENST00000563137.7	TSL:5 MANE Select	c.312C>T	p.Asp104Asp	synonymous	Exon 4 of 8	ENSP00000455588.3	A0A7P0Q1F0
	ZNF423	ENST00000562520.1	TSL:1	c.108C>T	p.Asp36Asp	synonymous	Exon 4 of 8	ENSP00000457664.1	Q2M1K9-2

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00393 AC: 957 AN: 243306 AF XY: 0.00423

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00196

Gnomad EAS exome AF: 0.0239

Gnomad FIN exome AF: 0.0000949

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00245 AC: 3559 AN: 1451782 Hom.: 21 Cov.: 35 AF XY: 0.00261 AC XY: 1879 AN XY: 720536

African (AFR) AF: 0.000420 AC: 14 AN: 33302

American (AMR) AF: 0.00131 AC: 58 AN: 44196

Ashkenazi Jewish (ASJ) AF: 0.00220 AC: 56 AN: 25448

East Asian (EAS) AF: 0.0149 AC: 589 AN: 39556

South Asian (SAS) AF: 0.00591 AC: 501 AN: 84788

European-Finnish (FIN) AF: 0.000283 AC: 15 AN: 53038

Middle Eastern (MID) AF: 0.00594 AC: 34 AN: 5724

European-Non Finnish (NFE) AF: 0.00193 AC: 2132 AN: 1105776

Other (OTH) AF: 0.00267 AC: 160 AN: 59954

GnomAD4 genome AF: 0.00204 AC: 310 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74452

African (AFR) AF: 0.000265 AC: 11 AN: 41570

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.0182 AC: 94 AN: 5176

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00253 Hom.: 0

Bravo AF: 0.00224

Asia WGS AF: 0.00549 AC: 19 AN: 3478

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)
-	-	1	ZNF423-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		4.5
Mutation Taster		=228/72	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: rs117266679; hg19: chr16-49672775;