rs781192528
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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R541H) has been classified as Uncertain significance.
Frequency
Consequence
NM_024741.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZNF408 | NM_024741.3 | c.1621C>T | p.Arg541Cys | missense_variant | 5/5 | ENST00000311764.3 | |
ZNF408 | NM_001184751.2 | c.1597C>T | p.Arg533Cys | missense_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZNF408 | ENST00000311764.3 | c.1621C>T | p.Arg541Cys | missense_variant | 5/5 | 1 | NM_024741.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000243 AC: 6AN: 246410Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134460
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1459592Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 726190
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
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 | Invitae | 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). - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 01, 2018 | - - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at