rs1057517928

chr10-69382591-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_001358263.1(HK1):c.1382C>T(p.Thr461Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T461K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HK1 NM_001358263.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001358263.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-69382591-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2506469.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, HK1
• PP5: Variant 10-69382591-C-T is Pathogenic according to our data. Variant chr10-69382591-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372693.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr10-69382591-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HK1	NM_001358263.1	c.1382C>T	p.Thr461Met	missense_variant	13/21	ENST00000643399.2
HK1	NM_000188.3	c.1370C>T	p.Thr457Met	missense_variant	10/18	ENST00000359426.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK1	ENST00000643399.2	c.1382C>T	p.Thr461Met	missense_variant	13/21		NM_001358263.1
HK1	ENST00000359426.7	c.1370C>T	p.Thr457Met	missense_variant	10/18	1	NM_000188.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with visual defects and brain anomalies Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 20, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2016	The T457M variant in the HK1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T457M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T457M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The T457M variant is a strong candidate for a pathogenic variant. -

Charcot-Marie-Tooth disease type 4G;C3150343:Hemolytic anemia due to hexokinase deficiency;C4479526:Retinitis pigmentosa 79 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1370C>T (p.T457M) alteration is located in coding exon 10 of the HK1 gene. This alteration results from a C to T substitution at nucleotide position 1370, causing the threonine (T) at amino acid position 457 to be replaced by a methionine (M). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the HK1 c.1370C>T alteration was not observed, with coverage at this position. The alteratione has been observed in affected individuals: _x000D_ _x000D_ This alteration was described to occur de novo in three individuals from two families with neurodevelopmental abnormalities. Common features included developmental delay, brain MRI anomalies, and optic atrophy. Additional issues included seizures, tone abnormalities, failure to thrive, swallowing and feeding difficulties, hearing loss, and laryngotracheomalacia (Okur, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.T457 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.T457M alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.89, 0.89, 0.88
MVP		0.53
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.68
gMVP		0.93

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: rs1057517928; hg19: chr10-71142347; COSMIC: COSV53863377;