chr11-86337359-C-T

Variant names:

• chr11-86337359-C-T
• rs115288922
• NM_016401.4:c.269-20C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016401.4(HIKESHI):​c.269-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,606,184 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (43 hom.)
• Consequence: HIKESHI NM_016401.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00300
• Publications: 0 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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• c11orf73-related autosomal recessive hypomyelinating leukodystrophy

  Inheritance: AR Classification: MODERATE Submitted by: Illumina

ENSG00000309946 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-86337359-C-T is Benign according to our data. Variant chr11-86337359-C-T is described in ClinVar as Benign. ClinVar VariationId is 1644219.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0134 (2046/152218) while in subpopulation AFR AF = 0.0472 (1959/41518). AF 95% confidence interval is 0.0454. There are 50 homozygotes in GnomAd4. There are 1018 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016401.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIKESHI	NM_016401.4	MANE Select	c.269-20C>T		intron	N/A	NP_057485.2
	HIKESHI	NM_001322404.2		c.269-20C>T		intron	N/A	NP_001309333.1
	HIKESHI	NM_001322407.2		c.152-20C>T		intron	N/A	NP_001309336.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIKESHI	ENST00000278483.8	TSL:1 MANE Select	c.269-20C>T		intron	N/A	ENSP00000278483.3	Q53FT3
	HIKESHI	ENST00000533986.5	TSL:1	c.269-20C>T		intron	N/A	ENSP00000432699.1	E9PPG8
	HIKESHI	ENST00000932066.1		c.269-26C>T		intron	N/A	ENSP00000602125.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2040 AN: 152100 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00347 AC: 850 AN: 245028 AF XY: 0.00265

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000630

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.00130 AC: 1889 AN: 1453966 Hom.: 43 Cov.: 30 AF XY: 0.00106 AC XY: 765 AN XY: 723012

African (AFR) AF: 0.0467 AC: 1549 AN: 33164

American (AMR) AF: 0.00257 AC: 112 AN: 43554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.0000945 AC: 8 AN: 84630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00110 AC: 6 AN: 5432

European-Non Finnish (NFE) AF: 0.0000370 AC: 41 AN: 1108576

Other (OTH) AF: 0.00288 AC: 173 AN: 60046

GnomAD4 genome AF: 0.0134 AC: 2046 AN: 152218 Hom.: 50 Cov.: 32 AF XY: 0.0137 AC XY: 1018 AN XY: 74412

African (AFR) AF: 0.0472 AC: 1959 AN: 41518

American (AMR) AF: 0.00425 AC: 65 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00354 Hom.: 1

Bravo AF: 0.0151

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.76
DANN	Benign	0.28
PhyloP100		0.0030
Mutation Taster		=100/0	polymorphism

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: rs115288922; hg19: chr11-86048401;