10-69295703-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001358263.1(HK1):c.75+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,446,312 control chromosomes in the GnomAD database, including 361,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.71 (38065 hom., cov: 31)
  • Exomes 𝑓: 0.71 (323493 hom.)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.701

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-69295703-T-C is Benign according to our data. Variant chr10-69295703-T-C is described in ClinVar as [Benign]. Clinvar id is 1285347.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK1	NM_001358263.1	c.75+23T>C		intron_variant		ENST00000643399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK1	ENST00000643399.2	c.75+23T>C		intron_variant			NM_001358263.1

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107123 AN: 151612 Hom.: 38046 Cov.: 31

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.708

GnomAD3 exomes AF: 0.698 AC: 169689 AN: 243094 Hom.: 59849 AF XY: 0.704 AC XY: 92459 AN XY: 131396

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.710

Gnomad EAS exome AF: 0.830

Gnomad SAS exome AF: 0.696

Gnomad FIN exome AF: 0.722

Gnomad NFE exome AF: 0.731

Gnomad OTH exome AF: 0.694

GnomAD4 exome AF: 0.709 AC: 918131 AN: 1294584 Hom.: 323493 Cov.: 21 AF XY: 0.711 AC XY: 463606 AN XY: 652334

Gnomad4 AFR exome AF: 0.651

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.704

Gnomad4 EAS exome AF: 0.850

Gnomad4 SAS exome AF: 0.696

Gnomad4 FIN exome AF: 0.722

Gnomad4 NFE exome AF: 0.715

Gnomad4 OTH exome AF: 0.706

GnomAD4 genome AF: 0.706 AC: 107180 AN: 151728 Hom.: 38065 Cov.: 31 AF XY: 0.702 AC XY: 52043 AN XY: 74122

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.608

Gnomad4 ASJ AF: 0.718

Gnomad4 EAS AF: 0.839

Gnomad4 SAS AF: 0.718

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.740

Gnomad4 OTH AF: 0.704

Alfa AF: 0.673 Hom.: 4344

Bravo AF: 0.692

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 79 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Hemolytic anemia due to hexokinase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Neurodevelopmental disorder with visual defects and brain anomalies Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Charcot-Marie-Tooth disease type 4G Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	7.7
Dann	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4746837; hg19: chr10-71055459; COSMIC: COSV64356366; COSMIC: COSV64356366;