rs781192528
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_024741.3(ZNF408):c.1621C>T(p.Arg541Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,459,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
ZNF408
NM_024741.3 missense
NM_024741.3 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 0.337
Genes affected
ZNF408 (HGNC:20041): (zinc finger protein 408) The protein encoded by this gene contains ten tandem zinc fingers and an N-terminal SET domain, so it is likely a DNA binding protein that interacts with other proteins. In adults, the encoded protein is expressed most highly in retina. Consequently, defects in this gene have been associated with familial exudative vitreoretinopathy (FEVR) and retinitis pigmentosa (RP). [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PP5
Variant 11-46705321-C-T is Pathogenic according to our data. Variant chr11-46705321-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46705321-C-T is described in Lovd as [Pathogenic]. Variant chr11-46705321-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZNF408 | NM_024741.3 | c.1621C>T | p.Arg541Cys | missense_variant | 5/5 | ENST00000311764.3 | NP_079017.1 | |
ZNF408 | NM_001184751.2 | c.1597C>T | p.Arg533Cys | missense_variant | 5/5 | NP_001171680.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZNF408 | ENST00000311764.3 | c.1621C>T | p.Arg541Cys | missense_variant | 5/5 | 1 | NM_024741.3 | ENSP00000309606.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000243 AC: 6AN: 246410Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134460
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1459592Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 726190
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinal dystrophy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2021 | - - |
Retinitis pigmentosa 72 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 24, 2023 | ClinVar contains an entry for this variant (Variation ID: 204317). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ZNF408 function (PMID: 25882705). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 541 of the ZNF408 protein (p.Arg541Cys). This variant is present in population databases (rs781192528, gnomAD 0.009%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 25882705; Invitae). - |
Retinitis pigmentosa 72;C4225316:Exudative vitreoretinopathy 6 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 01, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of disorder (P = 0.0508);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at