10-69292286-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000464803.6(HK1):c.56T>A(p.Leu19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 425,194 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/8 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: HK1 ENST00000464803.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.368

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=0.004175931).
• BP6: Variant 10-69292286-T-A is Benign according to our data. Variant chr10-69292286-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 811050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00231 (351/152224) while in subpopulation AMR AF= 0.0166 (253/15278). AF 95% confidence interval is 0.0149. There are 6 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK1	NM_001358263.1	c.28-3347T>A		intron_variant		ENST00000643399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK1	ENST00000643399.2	c.28-3347T>A		intron_variant			NM_001358263.1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152106 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00532 AC: 541 AN: 101734 Hom.: 13 AF XY: 0.00412 AC XY: 229 AN XY: 55636

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00290

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00235 AC: 641 AN: 272970 Hom.: 11 Cov.: 0 AF XY: 0.00184 AC XY: 286 AN XY: 155600

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.0240

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00335

Gnomad4 SAS exome AF: 0.000423

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00231 AC: 351 AN: 152224 Hom.: 6 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74450

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000933 Hom.: 1

Bravo AF: 0.00432

ExAC AF: 0.000276 AC: 4

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 30, 2023

- -

HK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.1
Dann	Uncertain	0.98
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
GERP RS		-0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs186567171; hg19: chr10-71052042;