rs1182983579
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001031710.3(KLHL7):āc.433A>Gā(p.Asn145Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N145Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001031710.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL7 | NM_001031710.3 | c.433A>G | p.Asn145Asp | missense_variant | 4/11 | ENST00000339077.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL7 | ENST00000339077.10 | c.433A>G | p.Asn145Asp | missense_variant | 4/11 | 1 | NM_001031710.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 152228Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 145 of the KLHL7 protein (p.Asn145Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 28041643, 31856884; Invitae). ClinVar contains an entry for this variant (Variation ID: 438051). 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. This variant disrupts the p.Asn145 amino acid residue in KLHL7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31856884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32581362, 31856884, 28041643, 31049658, 32531858) - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 21, 2019 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Retinitis pigmentosa 42 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The KLHL7 c.433A>G variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM1, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at