rs1054203

Positions:

• chr10-69395056-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001358263.1(HK1):​c.2338C>A​(p.Leu780Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HK1 NM_001358263.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HK1. . Trascript score misZ 5.1108 (greater than threshold 3.09). GenCC has associacion of gene with retinitis pigmentosa 79, non-spherocytic hemolytic anemia due to hexokinase deficiency, neurodevelopmental disorder with visual defects and brain anomalies, Charcot-Marie-Tooth disease type 4G.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HK1	NM_001358263.1	c.2338C>A	p.Leu780Met	missense_variant	19/21	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3	c.2326C>A	p.Leu776Met	missense_variant	16/18	ENST00000359426.7	NP_000179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.2338C>A	p.Leu780Met	missense_variant	19/21		NM_001358263.1	ENSP00000494664
HK1	ENST00000359426.7	c.2326C>A	p.Leu776Met	missense_variant	16/18	1	NM_000188.3	ENSP00000352398	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;.;.;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	.;.;N;.;N;N
REVEL	Pathogenic	0.76
Sift	Benign	0.036	.;.;D;.;D;D
Sift4G	Uncertain	0.015	.;D;D;.;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.70, 0.69, 0.69, 0.70
MVP		0.79
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1054203; hg19: chr10-71154812; COSMIC: COSV53856018;