10-69292327-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000464803.6(HK1):c.97C>T(p.Pro33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 437,766 control chromosomes in the GnomAD database, including 47,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/8 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14259 hom., cov: 32)
  • Exomes 𝑓: 0.47 (32911 hom.)
• Consequence: HK1 ENST00000464803.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.723563E-6).
• BP6: Variant 10-69292327-C-T is Benign according to our data. Variant chr10-69292327-C-T is described in ClinVar as [Benign]. Clinvar id is 993784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-69292327-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK1	NM_001358263.1	c.28-3306C>T		intron_variant		ENST00000643399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK1	ENST00000643399.2	c.28-3306C>T		intron_variant			NM_001358263.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61737 AN: 151886 Hom.: 14256 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.446

GnomAD3 exomes AF: 0.485 AC: 54452 AN: 112302 Hom.: 14160 AF XY: 0.475 AC XY: 29328 AN XY: 61704

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.589

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.465

Gnomad OTH exome AF: 0.490

GnomAD4 exome AF: 0.470 AC: 134282 AN: 285762 Hom.: 32911 Cov.: 0 AF XY: 0.463 AC XY: 75463 AN XY: 163124

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.641

Gnomad4 ASJ exome AF: 0.481

Gnomad4 EAS exome AF: 0.607

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.469

Gnomad4 NFE exome AF: 0.470

Gnomad4 OTH exome AF: 0.477

GnomAD4 genome AF: 0.406 AC: 61739 AN: 152004 Hom.: 14259 Cov.: 32 AF XY: 0.411 AC XY: 30560 AN XY: 74284

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.446

Alfa AF: 0.435 Hom.: 2878

Bravo AF: 0.408

TwinsUK AF: 0.488 AC: 1811

ALSPAC AF: 0.471 AC: 1816

ExAC AF: 0.364 AC: 5102

Asia WGS AF: 0.526 AC: 1828 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.95
Dann	Benign	0.44
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0000097	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P
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;