chr16-49635709-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001379286.1(ZNF423):​c.3467C>T​(p.Pro1156Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000066 in 1,604,970 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000070 ( 3 hom. )

Consequence

ZNF423
NM_001379286.1 missense

Scores

1
6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.33
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.051541895).
BP6
Variant 16-49635709-G-A is Benign according to our data. Variant chr16-49635709-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426244.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF423NM_001379286.1 linkc.3467C>T p.Pro1156Leu missense_variant Exon 4 of 8 ENST00000563137.7 NP_001366215.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF423ENST00000563137.7 linkc.3467C>T p.Pro1156Leu missense_variant Exon 4 of 8 5 NM_001379286.1 ENSP00000455588.3 A0A7P0Q1F0

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152124
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000133
AC:
32
AN:
240812
Hom.:
1
AF XY:
0.000145
AC XY:
19
AN XY:
130708
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000713
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000552
Gnomad OTH exome
AF:
0.000513
GnomAD4 exome
AF:
0.0000702
AC:
102
AN:
1452728
Hom.:
3
Cov.:
31
AF XY:
0.0000664
AC XY:
48
AN XY:
722802
show subpopulations
Gnomad4 AFR exome
AF:
0.0000606
Gnomad4 AMR exome
AF:
0.000640
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000470
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000451
Gnomad4 OTH exome
AF:
0.000117
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152242
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000670
Hom.:
0
Bravo
AF:
0.0000869
ExAC
AF:
0.000132
AC:
16

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 14, 2024The c.3443C>T (p.P1148L) alteration is located in exon 5 (coding exon 4) of the ZNF423 gene. This alteration results from a C to T substitution at nucleotide position 3443, causing the proline (P) at amino acid position 1148 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 25, 2017The P1148L variant in the ZNF423 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P1148L variant is observed in 14/11518 (0.12%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P1148L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P1148L as a variant of uncertain significance. -
Nephronophthisis 14 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 13, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.095
T;.;.;T;.;.;.
Eigen
Benign
-0.076
Eigen_PC
Benign
0.093
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
.;.;.;D;.;D;D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.052
T;T;T;T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Uncertain
2.4
M;.;.;M;.;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.7
D;D;D;D;D;D;D
REVEL
Benign
0.10
Sift
Uncertain
0.014
D;D;D;D;D;D;D
Sift4G
Benign
0.17
T;T;T;T;T;T;T
Polyphen
0.089
B;.;.;B;.;.;.
Vest4
0.28
MutPred
0.37
Loss of phosphorylation at T1147 (P = 0.0759);.;.;Loss of phosphorylation at T1147 (P = 0.0759);.;.;.;
MVP
0.068
MPC
0.40
ClinPred
0.13
T
GERP RS
5.0
Varity_R
0.14
gMVP
0.24

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756742718; hg19: chr16-49669620; API