chr16-49637266-T-C

Position:

• chr16-49637266-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379286.1(ZNF423):​c.1910A>G​(p.Asn637Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0293 in 1,614,178 control chromosomes in the GnomAD database, including 883 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (84 hom., cov: 33)
  • Exomes 𝑓: 0.029 (799 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.91

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020326376).
• BP6: Variant 16-49637266-T-C is Benign according to our data. Variant chr16-49637266-T-C is described in ClinVar as [Benign]. Clinvar id is 260524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-49637266-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF423	NM_001379286.1	c.1910A>G	p.Asn637Ser	missense_variant	4/8	ENST00000563137.7	NP_001366215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF423	ENST00000563137.7	c.1910A>G	p.Asn637Ser	missense_variant	4/8	5	NM_001379286.1	ENSP00000455588.3

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4309 AN: 152190 Hom.: 83 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0309 AC: 7768 AN: 251424 Hom.: 162 AF XY: 0.0331 AC XY: 4502 AN XY: 135910

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0566

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.0526

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.0320

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0294 AC: 42939 AN: 1461870 Hom.: 799 Cov.: 41 AF XY: 0.0307 AC XY: 22326 AN XY: 727230

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.0577

Gnomad4 EAS exome AF: 0.00605

Gnomad4 SAS exome AF: 0.0521

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0315

GnomAD4 genome AF: 0.0283 AC: 4306 AN: 152308 Hom.: 84 Cov.: 33 AF XY: 0.0294 AC XY: 2190 AN XY: 74484

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0185

Gnomad4 ASJ AF: 0.0611

Gnomad4 EAS AF: 0.0120

Gnomad4 SAS AF: 0.0446

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0321 Hom.: 101

Bravo AF: 0.0247

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.0187 AC: 82

ESP6500EA AF: 0.0320 AC: 275

ExAC AF: 0.0317 AC: 3852

Asia WGS AF: 0.0410 AC: 143 AN: 3478

EpiCase AF: 0.0326

EpiControl AF: 0.0343

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.078	T;.;.;T;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	.;.;.;T;.;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;.;.;N;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.59	N;N;N;N;N;N;N
REVEL	Benign	0.094
Sift	Benign	0.73	T;T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T
Polyphen		0.0020	B;.;.;B;.;.;.
Vest4		0.20
MPC		0.30
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.084
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs34214571; hg19: chr16-49671177; COSMIC: COSV52206290;