dbSNP rs6592284: HIKESHI:c.*92T>C (chr11-86344859-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000533986.5(HIKESHI):c.*92T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 613,048 control chromosomes in the GnomAD database, including 13,883 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4864 hom., cov: 32)

Exomes 𝑓: 0.19 ( 9019 hom. )

Consequence

HIKESHI
ENST00000533986.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.976

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 13
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
c11orf73-related autosomal recessive hypomyelinating leukodystrophy
Inheritance: AR Classification: MODERATE Submitted by: Illumina

HIKESHI links:

ENSG00000309946 (HGNC:):

ENSG00000309946 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIKESHI	NM_016401.4 link	c.539+138T>C		intron_variant	Intron 4 of 4	ENST00000278483.8	NP_057485.2	Q53FT3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIKESHI	ENST00000278483.8 link	c.539+138T>C		intron_variant	Intron 4 of 4	1	NM_016401.4	ENSP00000278483.3		Q53FT3

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34455

AN:

152076

Hom.:

4866

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.0674

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.206

GnomAD4 exome

AF:

0.186

AC:

85921

AN:

460854

Hom.:

9019

Cov.:

AF XY:

0.188

AC XY:

45400

AN XY:

241548

show subpopulations

African (AFR)

AF:

0.383

AC:

4756

AN:

12404

American (AMR)

AF:

0.272

AC:

5138

AN:

18858

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

1898

AN:

13270

East Asian (EAS)

AF:

0.338

AC:

10310

AN:

30518

South Asian (SAS)

AF:

0.275

AC:

9978

AN:

36250

European-Finnish (FIN)

AF:

0.0825

AC:

3271

AN:

39660

Middle Eastern (MID)

AF:

0.211

AC:

536

AN:

2544

European-Non Finnish (NFE)

AF:

0.159

AC:

44988

AN:

282086

Other (OTH)

AF:

0.200

AC:

5046

AN:

25264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3579

7158

10736

14315

17894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.226

AC:

34470

AN:

152194

Hom.:

4864

Cov.:

AF XY:

0.225

AC XY:

16738

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.379

AC:

15730

AN:

41508

American (AMR)

AF:

0.231

AC:

3533

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

441

AN:

3468

East Asian (EAS)

AF:

0.370

AC:

1912

AN:

5164

South Asian (SAS)

AF:

0.254

AC:

1224

AN:

4828

European-Finnish (FIN)

AF:

0.0674

AC:

715

AN:

10614

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.150

AC:

10226

AN:

68006

Other (OTH)

AF:

0.203

AC:

430

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1257

2514

3772

5029

6286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.180

Hom.:

12467

Bravo

AF:

0.247

Asia WGS

AF:

0.292

AC:

1015

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.6

(source)

DANN

Benign

0.55

PhyloP100

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs6592284

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over