rs17476364

Variant names:

• chr10-69334748-T-C
• rs17476364
• NM_001358263.1:c.76-9079T>C

Variant summary

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

The NM_001358263.1(HK1):​c.76-9079T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 152,186 control chromosomes in the GnomAD database, including 427 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 0.064 (427 hom., cov: 32)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• Publications: 26 publications found

Genes affected

HK1 (HGNC:4922): (hexokinase 1) Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in several transcript variants which encode different isoforms, some of which are tissue-specific. [provided by RefSeq, Apr 2016]

HK1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with visual defects and brain anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 79

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• non-spherocytic hemolytic anemia due to hexokinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Charcot-Marie-Tooth disease type 4G

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.76-9079T>C		intron_variant	Intron 4 of 20	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3	c.64-9079T>C		intron_variant	Intron 1 of 17	ENST00000359426.7	NP_000179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.76-9079T>C		intron_variant	Intron 4 of 20		NM_001358263.1	ENSP00000494664.1
HK1	ENST00000359426.7	c.64-9079T>C		intron_variant	Intron 1 of 17	1	NM_000188.3	ENSP00000352398.6

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9713 AN: 152068 Hom.: 429 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0980

Gnomad OTH AF: 0.0714

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0638 AC: 9707 AN: 152186 Hom.: 427 Cov.: 32 AF XY: 0.0610 AC XY: 4539 AN XY: 74400

African (AFR) AF: 0.0183 AC: 761 AN: 41544

American (AMR) AF: 0.0717 AC: 1096 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5160

South Asian (SAS) AF: 0.0331 AC: 160 AN: 4828

European-Finnish (FIN) AF: 0.0506 AC: 537 AN: 10614

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0980 AC: 6658 AN: 67972

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0713 Hom.: 61

Bravo AF: 0.0645

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs17476364; hg19: chr10-71094504;