16-49635840-C-T

Variant names:

• chr16-49635840-C-T
• rs61739947
• NM_001379286.1:c.3336G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001379286.1(ZNF423):​c.3336G>A​(p.Val1112Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,603,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ZNF423 NM_001379286.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 0 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 -8 ACMG points.

• BP6: Variant 16-49635840-C-T is Benign according to our data. Variant chr16-49635840-C-T is described in ClinVar as Benign. ClinVar VariationId is 473062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	NM_001379286.1	MANE Select	c.3336G>A	p.Val1112Val	synonymous	Exon 4 of 8	NP_001366215.1
	ZNF423	NM_015069.5		c.3312G>A	p.Val1104Val	synonymous	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.3132G>A	p.Val1044Val	synonymous	Exon 4 of 8	NP_001258549.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	ENST00000563137.7	TSL:5 MANE Select	c.3336G>A	p.Val1112Val	synonymous	Exon 4 of 8	ENSP00000455588.3
	ZNF423	ENST00000562520.1	TSL:1	c.3132G>A	p.Val1044Val	synonymous	Exon 4 of 8	ENSP00000457664.1
	ZNF423	ENST00000567169.5	TSL:1	c.2961G>A	p.Val987Val	synonymous	Exon 2 of 6	ENSP00000455061.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000385 AC: 90 AN: 233806 AF XY: 0.000235

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.000743

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000116 AC: 168 AN: 1451098 Hom.: 0 Cov.: 31 AF XY: 0.0000956 AC XY: 69 AN XY: 721532

African (AFR) AF: 0.00312 AC: 103 AN: 33046

American (AMR) AF: 0.000632 AC: 27 AN: 42692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25424

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 84948

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51804

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5712

European-Non Finnish (NFE) AF: 0.0000181 AC: 20 AN: 1107960

Other (OTH) AF: 0.000267 AC: 16 AN: 59910

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74482

African (AFR) AF: 0.00454 AC: 189 AN: 41586

American (AMR) AF: 0.00209 AC: 32 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000486 Hom.: 0

Bravo AF: 0.00166

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.67
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61739947; hg19: chr16-49669751;