10-69288744-A-G

Position:

• chr10-69288744-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001358263.1(HK1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HK1 NM_001358263.1 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.39

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-69288744-A-G is Pathogenic according to our data. Variant chr10-69288744-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 802580.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HK1	NM_001358263.1	c.1A>G	p.Met1?	start_lost	3/21	ENST00000643399.2	NP_001345192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.1A>G	p.Met1?	start_lost	3/21		NM_001358263.1	ENSP00000494664

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4G Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	0.10
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;.
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationTaster	Benign	0.97	D;D
PROVEAN	Benign	-1.1	N;N;N;.;.;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;.;.;.
Sift4G	Benign	0.72	.;T;D;.;.;.
Polyphen		0.45	B;.;B;.;.;B
Vest4		0.86
MutPred		0.60		Loss of catalytic residue at M1 (P = 0.0295);Loss of catalytic residue at M1 (P = 0.0295);Loss of catalytic residue at M1 (P = 0.0295);Loss of catalytic residue at M1 (P = 0.0295);Loss of catalytic residue at M1 (P = 0.0295);Loss of catalytic residue at M1 (P = 0.0295);
MVP		0.81
ClinPred		0.99	D
GERP RS		4.1
gMVP		0.65

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1589439508; hg19: chr10-71048500;