rs1057517928

Variant names:

• chr10-69382591-C-A
• rs1057517928
• NM_001358263.1:c.1382C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-69382591-C-A
• chr10-69382591-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_001358263.1(HK1):​c.1382C>A​(p.Thr461Lys) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T461M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HK1 NM_001358263.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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]

HK1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with visual defects and brain anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 79

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• non-spherocytic hemolytic anemia due to hexokinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Charcot-Marie-Tooth disease type 4G

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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, 5 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-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 10-69382591-C-A is Pathogenic according to our data. Variant chr10-69382591-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2506469.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.1382C>A	p.Thr461Lys	missense_variant	Exon 13 of 21	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3	c.1370C>A	p.Thr457Lys	missense_variant	Exon 10 of 18	ENST00000359426.7	NP_000179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.1382C>A	p.Thr461Lys	missense_variant	Exon 13 of 21		NM_001358263.1	ENSP00000494664.1
HK1	ENST00000359426.7	c.1370C>A	p.Thr457Lys	missense_variant	Exon 10 of 18	1	NM_000188.3	ENSP00000352398.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with visual defects and brain anomalies Pathogenic:1

Nov 03, 2022

Eurofins-Biomnis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;.;.;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D;D;.;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.5	.;.;.;.;.;H
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	.;.;D;.;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	.;.;D;.;D;D
Sift4G	Uncertain	0.013	.;D;D;.;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.91, 0.91, 0.93, 0.92
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		0.92
gMVP		0.98
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs1057517928; hg19: chr10-71142347;