rs6592284

Variant names:

• chr11-86344859-T-C
• rs6592284
• ENST00000533986.5:c.*92T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.976
• Publications: 23 publications found

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

ENSG00000309946 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000533986.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIKESHI	NM_016401.4	MANE Select	c.539+138T>C		intron	N/A	NP_057485.2
	HIKESHI	NM_001322404.2		c.479+138T>C		intron	N/A	NP_001309333.1
	HIKESHI	NM_001322407.2		c.422+138T>C		intron	N/A	NP_001309336.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIKESHI	ENST00000533986.5	TSL:1	c.*92T>C		3_prime_UTR	Exon 4 of 4	ENSP00000432699.1
	HIKESHI	ENST00000278483.8	TSL:1 MANE Select	c.539+138T>C		intron	N/A	ENSP00000278483.3
	HIKESHI	ENST00000932066.1		c.533+138T>C		intron	N/A	ENSP00000602125.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34455 AN: 152076 Hom.: 4866 Cov.: 32

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.: 6 AF XY: 0.188 AC XY: 45400 AN XY: 241548

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

GnomAD4 genome AF: 0.226 AC: 34470 AN: 152194 Hom.: 4864 Cov.: 32 AF XY: 0.225 AC XY: 16738 AN XY: 74418

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: 57 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10226 AN: 68006

Other (OTH) AF: 0.203 AC: 430 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.6
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)

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

Other links and lift over

dbSNP: rs6592284; hg19: chr11-86055901; COSMIC: COSV53575132;