chr11-86306279-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016401.4(HIKESHI):c.65A>C(p.Lys22Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
HIKESHI
NM_016401.4 missense
NM_016401.4 missense
Scores
4
9
3
Clinical Significance
Conservation
PhyloP100: 8.71
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HIKESHI | NM_016401.4 | c.65A>C | p.Lys22Thr | missense_variant | 2/5 | ENST00000278483.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HIKESHI | ENST00000278483.8 | c.65A>C | p.Lys22Thr | missense_variant | 2/5 | 1 | NM_016401.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251372Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135860
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461544Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727030
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74484
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2021 | The c.65A>C (p.K22T) alteration is located in exon 2 (coding exon 2) of the HIKESHI gene. This alteration results from a A to C substitution at nucleotide position 65, causing the lysine (K) at amino acid position 22 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 22 of the HIKESHI protein (p.Lys22Thr). This variant is present in population databases (rs201239774, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with HIKESHI-related conditions. ClinVar contains an entry for this variant (Variation ID: 1422008). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.68
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