rs1133189

Positions:

• chr10-69343841-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001358263.1(HK1):​c.90C>G​(p.Leu30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,610,334 control chromosomes in the GnomAD database, including 109,887 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10109 hom., cov: 31)
  • Exomes 𝑓: 0.36 (99778 hom.)
• Consequence: HK1 NM_001358263.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.347

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 10-69343841-C-G is Benign according to our data. Variant chr10-69343841-C-G is described in ClinVar as [Benign]. Clinvar id is 439787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-69343841-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.347 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK1	NM_001358263.1	c.90C>G	p.Leu30=	synonymous_variant	5/21	ENST00000643399.2
HK1	NM_000188.3	c.78C>G	p.Leu26=	synonymous_variant	2/18	ENST00000359426.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK1	ENST00000643399.2	c.90C>G	p.Leu30=	synonymous_variant	5/21		NM_001358263.1
HK1	ENST00000359426.7	c.78C>G	p.Leu26=	synonymous_variant	2/18	1	NM_000188.3	P1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54245 AN: 151800 Hom.: 10103 Cov.: 31

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.327

GnomAD3 exomes AF: 0.314 AC: 78903 AN: 251444 Hom.: 13691 AF XY: 0.317 AC XY: 43142 AN XY: 135892

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.272

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.383

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.363 AC: 529833 AN: 1458416 Hom.: 99778 Cov.: 34 AF XY: 0.361 AC XY: 262098 AN XY: 725694

Gnomad4 AFR exome AF: 0.402

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.364

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.357 AC: 54285 AN: 151918 Hom.: 10109 Cov.: 31 AF XY: 0.352 AC XY: 26147 AN XY: 74236

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.330

Alfa AF: 0.363 Hom.: 3441

Bravo AF: 0.351

Asia WGS AF: 0.234 AC: 814 AN: 3478

EpiCase AF: 0.367

EpiControl AF: 0.365

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

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	-0.39
CADD	Benign	9.6
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1133189; hg19: chr10-71103597; COSMIC: COSV53853227; COSMIC: COSV53853227;