16-49635996-C-T

Variant names:

• chr16-49635996-C-T
• rs117592972
• NM_001379286.1:c.3180G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001379286.1(ZNF423):​c.3180G>A​(p.Ala1060Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000715 in 1,602,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.88
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-49635996-C-T is Benign according to our data. Variant chr16-49635996-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.88 with no splicing effect.

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.3180G>A	p.Ala1060Ala	synonymous	Exon 4 of 8	NP_001366215.1	A0A7P0Q1F0
	ZNF423	NM_015069.5		c.3156G>A	p.Ala1052Ala	synonymous	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.2976G>A	p.Ala992Ala	synonymous	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.3180G>A	p.Ala1060Ala	synonymous	Exon 4 of 8	ENSP00000455588.3	A0A7P0Q1F0
	ZNF423	ENST00000562520.1	TSL:1	c.2976G>A	p.Ala992Ala	synonymous	Exon 4 of 8	ENSP00000457664.1	Q2M1K9-2
	ZNF423	ENST00000567169.5	TSL:1	c.2805G>A	p.Ala935Ala	synonymous	Exon 2 of 6	ENSP00000455061.1	F5H7S1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00114 AC: 276 AN: 242938 AF XY: 0.00101

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0129

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000228

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000729 AC: 1057 AN: 1449778 Hom.: 1 Cov.: 31 AF XY: 0.000676 AC XY: 486 AN XY: 719248

African (AFR) AF: 0.000180 AC: 6 AN: 33322

American (AMR) AF: 0.0000677 AC: 3 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25476

East Asian (EAS) AF: 0.00952 AC: 376 AN: 39486

South Asian (SAS) AF: 0.000248 AC: 21 AN: 84586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52674

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5704

European-Non Finnish (NFE) AF: 0.000557 AC: 615 AN: 1104374

Other (OTH) AF: 0.000551 AC: 33 AN: 59864

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74468

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

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5174

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.000740

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Nephronophthisis 14 (1)
-	-	1	not provided (1)
-	-	1	ZNF423-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.041
DANN	Benign	0.39
PhyloP100		-3.9
Mutation Taster		=99/1	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: rs117592972; hg19: chr16-49669907; COSMIC: COSV52200950;