rs202003795
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_016401.4(HIKESHI):āc.160G>Cā(p.Val54Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,613,666 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Genomes: š 0.000092 ( 0 hom., cov: 32)
Exomes š: 0.000089 ( 1 hom. )
Consequence
HIKESHI
NM_016401.4 missense
NM_016401.4 missense
Scores
2
10
4
Clinical Significance
Conservation
PhyloP100: 9.39
Genes affected
HIKESHI (HGNC:26938): (heat shock protein nuclear import factor hikeshi) This gene encodes an evolutionarily conserved nuclear transport receptor that mediates heat-shock-induced nuclear import of 70 kDa heat-shock proteins (Hsp70s) through interactions with FG-nucleoporins. The protein mediates transport of the ATP form but not the ADP form of Hsp70 proteins under conditions of heat shock stress. Structural analyses demonstrate that the protein forms an asymmetric homodimer and that the N-terminal domain consists of a jelly-roll/beta-sandwich fold structure that contains hydrophobic pockets involved in FG-nucleoporin recognition. Reduction of RNA expression levels in HeLa cells using small interfering RNAs results in inhibition of heat shock-induced nuclear accumulation of Hsp70s, indicating a role for this gene in regulation of Hsp70 nuclear import during heat shock stress. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-86306374-G-C is Pathogenic according to our data. Variant chr11-86306374-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 224891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.17225519). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HIKESHI | NM_016401.4 | c.160G>C | p.Val54Leu | missense_variant | 2/5 | ENST00000278483.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HIKESHI | ENST00000278483.8 | c.160G>C | p.Val54Leu | missense_variant | 2/5 | 1 | NM_016401.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000143 AC: 36AN: 251456Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135902
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GnomAD4 exome AF: 0.0000889 AC: 130AN: 1461506Hom.: 1 Cov.: 31 AF XY: 0.000106 AC XY: 77AN XY: 727098
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74330
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypomyelinating leukodystrophy 13 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 09, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HIKESHI function (PMID: 26545878). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 224891). This missense change has been observed in individual(s) with congenital leukodystrophy (PMID: 26545878, 31912665). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs202003795, gnomAD 0.3%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 54 of the HIKESHI protein (p.Val54Leu). - |
HIKESHI-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 13, 2023 | The HIKESHI c.160G>C variant is predicted to result in the amino acid substitution p.Val54Leu. This variant has been reported in the homozygous state in multiple individuals with hypomyelinating leukodystrophy-13, and segregated with disease in families (Edvardson et al. 2016. PubMed ID: 26545878). In addition, Edvardson et al. demonstrated that homozygous patients had undetectable levels of the HIKESHI protein in fibroblasts. This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-86017416-G-C). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Uncertain
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
MPC
0.47
ClinPred
D
GERP RS
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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