rs547547946
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_006063.3(KLHL41):c.175C>T(p.Arg59Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000458 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59H) has been classified as Uncertain significance.
Frequency
Consequence
NM_006063.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL41 | NM_006063.3 | c.175C>T | p.Arg59Cys | missense_variant | 1/6 | ENST00000284669.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL41 | ENST00000284669.2 | c.175C>T | p.Arg59Cys | missense_variant | 1/6 | 1 | NM_006063.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251430Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135892
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33AN XY: 727228
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74428
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 22, 2023 | PM2 - |
Nemaline myopathy 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 59 of the KLHL41 protein (p.Arg59Cys). This variant is present in population databases (rs547547946, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with KLHL41-related conditions. ClinVar contains an entry for this variant (Variation ID: 474868). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KLHL41 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at