rs397509419
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_152393.4(KLHL40):c.1582G>A(p.Glu528Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,776 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
KLHL40
NM_152393.4 missense
NM_152393.4 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 9.84
Genes affected
KLHL40 (HGNC:30372): (kelch like family member 40) This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a repeat Kelch 4 (size 45) in uniprot entity KLH40_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_152393.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.922
PP5
?
Variant 3-42689029-G-A is Pathogenic according to our data. Variant chr3-42689029-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-42689029-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL40 | NM_152393.4 | c.1582G>A | p.Glu528Lys | missense_variant | 4/6 | ENST00000287777.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL40 | ENST00000287777.5 | c.1582G>A | p.Glu528Lys | missense_variant | 4/6 | 1 | NM_152393.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250842Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135528
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461574Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727064
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nemaline myopathy 8 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 20, 2022 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 528 of the KLHL40 protein (p.Glu528Lys). This variant is present in population databases (rs397509419, gnomAD 0.09%). This missense change has been observed in individuals with nemaline myopathy (PMID: 23746549). ClinVar contains an entry for this variant (Variation ID: 60512). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change alters KLHL40 gene expression (PMID: 24960163). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic supporitng evidence (ClinVar ID: VCV000060512.2, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000637, PM2). The variant was observed in trans with a pathogenic variant (NM_152393.3:c.1281_1294del) as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.875, PP3). Patient's phenotype is considered compatible with Nemaline myopathy 8, autosomal recessive (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of ubiquitination at E528 (P = 0.0203);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at