16-49523571-C-T

Variant names:

• chr16-49523571-C-T
• rs2287314
• NM_001379286.1:c.3849+53G>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.3849+53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,510,192 control chromosomes in the GnomAD database, including 224,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28056 hom., cov: 34)
  • Exomes 𝑓: 0.54 (196660 hom.)
• Consequence: ZNF423 NM_001379286.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.70
• Publications: 9 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=-0.98).
• BP6: Variant 16-49523571-C-T is Benign according to our data. Variant chr16-49523571-C-T is described in ClinVar as [Benign]. Clinvar id is 1245209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.3849+53G>A		intron_variant	Intron 7 of 7	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7	c.3849+53G>A		intron_variant	Intron 7 of 7	5	NM_001379286.1	ENSP00000455588.3

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90771 AN: 152034 Hom.: 28010 Cov.: 34

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.603

GnomAD4 exome AF: 0.536 AC: 727625 AN: 1358040 Hom.: 196660 AF XY: 0.532 AC XY: 362172 AN XY: 680402

African (AFR) AF: 0.759 AC: 23863 AN: 31424

American (AMR) AF: 0.480 AC: 21098 AN: 43954

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 15295 AN: 25328

East Asian (EAS) AF: 0.487 AC: 19045 AN: 39144

South Asian (SAS) AF: 0.462 AC: 38614 AN: 83634

European-Finnish (FIN) AF: 0.553 AC: 28904 AN: 52298

Middle Eastern (MID) AF: 0.575 AC: 3201 AN: 5568

European-Non Finnish (NFE) AF: 0.536 AC: 546352 AN: 1019758

Other (OTH) AF: 0.549 AC: 31253 AN: 56932

GnomAD4 genome AF: 0.597 AC: 90880 AN: 152152 Hom.: 28056 Cov.: 34 AF XY: 0.593 AC XY: 44130 AN XY: 74382

African (AFR) AF: 0.753 AC: 31289 AN: 41534

American (AMR) AF: 0.535 AC: 8174 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2113 AN: 3472

East Asian (EAS) AF: 0.509 AC: 2630 AN: 5164

South Asian (SAS) AF: 0.459 AC: 2211 AN: 4816

European-Finnish (FIN) AF: 0.556 AC: 5884 AN: 10574

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36551 AN: 67982

Other (OTH) AF: 0.608 AC: 1286 AN: 2114

Alfa AF: 0.484 Hom.: 1912

Bravo AF: 0.606

Asia WGS AF: 0.536 AC: 1865 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.0010
DANN	Benign	0.78
PhyloP100		-3.7
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: rs2287314; hg19: chr16-49557482; COSMIC: COSV52181807; COSMIC: COSV52181807;