rs10159477

Variant names:

• chr10-69340132-G-A
• rs10159477
• NM_001358263.1:c.76-3695G>A

Variant summary

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

The NM_001358263.1(HK1):​c.76-3695G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,162 control chromosomes in the GnomAD database, including 1,519 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 0.13 (1519 hom., cov: 33)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30
• Publications: 32 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358263.1. 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
	HK1	NM_001358263.1	MANE Plus Clinical	c.76-3695G>A		intron	N/A	NP_001345192.1
	HK1	NM_000188.3	MANE Select	c.64-3695G>A		intron	N/A	NP_000179.2
	HK1	NM_001322365.2		c.169-3695G>A		intron	N/A	NP_001309294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000643399.2	MANE Plus Clinical	c.76-3695G>A		intron	N/A	ENSP00000494664.1
	HK1	ENST00000359426.7	TSL:1 MANE Select	c.64-3695G>A		intron	N/A	ENSP00000352398.6
	HK1	ENST00000464803.6	TSL:1	c.169-3695G>A		intron	N/A	ENSP00000496531.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20438 AN: 152044 Hom.: 1519 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0764

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.134 AC: 20444 AN: 152162 Hom.: 1519 Cov.: 33 AF XY: 0.131 AC XY: 9763 AN XY: 74382

African (AFR) AF: 0.159 AC: 6600 AN: 41496

American (AMR) AF: 0.115 AC: 1759 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.129 AC: 621 AN: 4822

European-Finnish (FIN) AF: 0.0764 AC: 809 AN: 10586

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9710 AN: 68004

Other (OTH) AF: 0.132 AC: 279 AN: 2116

Alfa AF: 0.152 Hom.: 8709

Bravo AF: 0.138

Asia WGS AF: 0.0660 AC: 231 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0060
DANN	Benign	0.77
PhyloP100		-2.3
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: rs10159477; hg19: chr10-71099888;