chr10-69382591-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP5
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
NM_001358263.1 missense
Scores
4
5
3
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurodevelopmental disorder with visual defects and brain anomalies Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 20, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 22, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 20, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Feb 06, 2020 | - - |
not provided Pathogenic:2
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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2020 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
D;D;D;D;D;D
Vest4
0.89, 0.89, 0.88
MVP
0.53
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at