rs202003795

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_016401.4(HIKESHI):c.160G>C(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 (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 1 hom. )

Consequence

HIKESHI
NM_016401.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.39

Variant links:

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]

HIKESHI links:

Genome browser will be placed here

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 rank	MANE	Protein	UniProt
HIKESHI	NM_016401.4 link	c.160G>C	p.Val54Leu	missense_variant	Exon 2 of 5	ENST00000278483.8	NP_057485.2	Q53FT3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIKESHI	ENST00000278483.8 link	c.160G>C	p.Val54Leu	missense_variant	Exon 2 of 5	1	NM_016401.4	ENSP00000278483.3		Q53FT3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251456

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461506

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000319

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 13

Pathogenic:2

Aug 09, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HIKESHI c.160G>C (p.Val54Leu) results in a conservative amino acid change located in the Hikeshi-like, N-terminal domain (IPR008493) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a global frequency of 8.9e-05 and at a frequency of 0.003 among the Ashkenazi-Jewish subpopulation (including 1 homozygote) in 1613666 control chromosomes in the gnomAD database. This variant has been proposed as a founder variant among individuals of Ashkenazi-Jewish descent (example, Edvardson_2016, Helman_2021). c.160G>C has been reported in the literature in numerous homozygous individuals affected with Hypomyelinating Leukodystrophy 13 (example, Edvardson_2016, Helman_2020, Helman_2021, Sukenik-Halevy_2022). These data indicate that the variant is very likely to be associated with disease. In patient-derived fibroblasts, this variant was associated with undetectable levels of HIKESHI-encoded protein (example, Edvardson_2016) however follow up experiments in rat oligodendrocytes did not find any impact to protein expression (example, Miyamoto_2023). Markers of rat oligodendrocyte differentiation were reduced vs. wild type in this model (example, Miyamoto_2023). The following publications have been ascertained in the context of this evaluation (PMID: 26545878, 31912665, 34111619, 37965292, 35032046, 37267771). ClinVar contains an entry for this variant (Variation ID: 224891). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs202003795, gnomAD 0.3%). 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. ClinVar contains an entry for this variant (Variation ID: 224891). 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 tolerated. Experimental studies have shown that this missense change affects HIKESHI function (PMID: 26545878). For these reasons, this variant has been classified as Pathogenic. -

HIKESHI-related disorder

Pathogenic:1

Jun 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Pathogenic

3.2

.;M

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.29

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.46

P;P

Vest4

0.85

MVP

0.60

MPC

0.47

ClinPred

0.74

GERP RS

4.9

Varity_R

0.82

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over