rs2292155

Variant names:

• chr16-49731037-C-T
• rs2292155
• NM_001379286.1:c.101-66G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379286.1(ZNF423):​c.101-66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,551,884 control chromosomes in the GnomAD database, including 105,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11717 hom., cov: 32)
  • Exomes 𝑓: 0.36 (93876 hom.)
• Consequence: ZNF423 NM_001379286.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.15
• Publications: 11 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: AD, Unknown, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Joubert syndrome with oculorenal defect

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

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

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-49731037-C-T is Benign according to our data. Variant chr16-49731037-C-T is described in ClinVar as [Benign]. Clinvar id is 1239696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.101-66G>A		intron_variant	Intron 2 of 7	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7	c.101-66G>A		intron_variant	Intron 2 of 7	5	NM_001379286.1	ENSP00000455588.3

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58601 AN: 151914 Hom.: 11702 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.362 AC: 506790 AN: 1399852 Hom.: 93876 AF XY: 0.359 AC XY: 250181 AN XY: 696176

African (AFR) AF: 0.487 AC: 15551 AN: 31936

American (AMR) AF: 0.236 AC: 10144 AN: 43058

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 8722 AN: 25088

East Asian (EAS) AF: 0.216 AC: 8455 AN: 39150

South Asian (SAS) AF: 0.284 AC: 23680 AN: 83444

European-Finnish (FIN) AF: 0.363 AC: 18870 AN: 51942

Middle Eastern (MID) AF: 0.261 AC: 1447 AN: 5534

European-Non Finnish (NFE) AF: 0.376 AC: 399033 AN: 1061640

Other (OTH) AF: 0.360 AC: 20888 AN: 58060

GnomAD4 genome AF: 0.386 AC: 58647 AN: 152032 Hom.: 11717 Cov.: 32 AF XY: 0.383 AC XY: 28480 AN XY: 74282

African (AFR) AF: 0.486 AC: 20153 AN: 41464

American (AMR) AF: 0.311 AC: 4754 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1219 AN: 3472

East Asian (EAS) AF: 0.246 AC: 1273 AN: 5176

South Asian (SAS) AF: 0.290 AC: 1398 AN: 4816

European-Finnish (FIN) AF: 0.355 AC: 3742 AN: 10530

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24895 AN: 67974

Other (OTH) AF: 0.360 AC: 761 AN: 2114

Alfa AF: 0.371 Hom.: 46793

Bravo AF: 0.388

Asia WGS AF: 0.253 AC: 884 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.77
PhyloP100		-1.1
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: rs2292155; hg19: chr16-49764948; COSMIC: COSV52190317;