rs748235

chr10-69382664-G-Achr10-69382664-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001358263.1(HK1):c.1455G>A(p.Lys485=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,684 control chromosomes in the GnomAD database, including 505,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49185 hom., cov: 32)
  • Exomes 𝑓: 0.79 (455844 hom.)
• Consequence: HK1 NM_001358263.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.894

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-69382664-G-A is Benign according to our data. Variant chr10-69382664-G-A is described in ClinVar as [Benign]. Clinvar id is 255483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-69382664-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.894 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK1	NM_001358263.1	c.1455G>A	p.Lys485=	synonymous_variant	13/21	ENST00000643399.2
HK1	NM_000188.3	c.1443G>A	p.Lys481=	synonymous_variant	10/18	ENST00000359426.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK1	ENST00000643399.2	c.1455G>A	p.Lys485=	synonymous_variant	13/21		NM_001358263.1
HK1	ENST00000359426.7	c.1443G>A	p.Lys481=	synonymous_variant	10/18	1	NM_000188.3	P1

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121654 AN: 152012 Hom.: 49144 Cov.: 32

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.902

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.805

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.788

GnomAD3 exomes AF: 0.772 AC: 193253 AN: 250250 Hom.: 75900 AF XY: 0.784 AC XY: 105983 AN XY: 135262

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.834

Gnomad EAS exome AF: 0.681

Gnomad SAS exome AF: 0.890

Gnomad FIN exome AF: 0.799

Gnomad NFE exome AF: 0.790

Gnomad OTH exome AF: 0.763

GnomAD4 exome AF: 0.787 AC: 1150645 AN: 1461554 Hom.: 455844 Cov.: 67 AF XY: 0.791 AC XY: 575295 AN XY: 727088

Gnomad4 AFR exome AF: 0.891

Gnomad4 AMR exome AF: 0.582

Gnomad4 ASJ exome AF: 0.834

Gnomad4 EAS exome AF: 0.581

Gnomad4 SAS exome AF: 0.890

Gnomad4 FIN exome AF: 0.795

Gnomad4 NFE exome AF: 0.790

Gnomad4 OTH exome AF: 0.796

GnomAD4 genome AF: 0.800 AC: 121755 AN: 152130 Hom.: 49185 Cov.: 32 AF XY: 0.798 AC XY: 59392 AN XY: 74382

Gnomad4 AFR AF: 0.880

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.834

Gnomad4 EAS AF: 0.647

Gnomad4 SAS AF: 0.884

Gnomad4 FIN AF: 0.805

Gnomad4 NFE AF: 0.785

Gnomad4 OTH AF: 0.791

Alfa AF: 0.786 Hom.: 104859

Bravo AF: 0.791

Asia WGS AF: 0.780 AC: 2712 AN: 3478

EpiCase AF: 0.788

EpiControl AF: 0.795

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	11
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs748235; hg19: chr10-71142420; COSMIC: COSV53863345;