10-69292327-C-A

Variant names:

• chr10-69292327-C-A
• rs4746836
• ENST00000464803.6:c.97C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001322365.2(HK1):​c.97C>A​(p.Pro33Thr) 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 benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HK1 NM_001322365.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the HK1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Trascript score misZ: 5.1108 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08307949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.28-3306C>A		intron_variant	Intron 3 of 20	ENST00000643399.2	NP_001345192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.28-3306C>A		intron_variant	Intron 3 of 20		NM_001358263.1	ENSP00000494664.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 287148 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 163944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.62
DANN	Benign	0.73
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.98	T
MutPred		0.44		Loss of glycosylation at P34 (P = 0.0514);
GERP RS		-1.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4746836; hg19: chr10-71052083;