10-69288744-A-G

Variant names:

• chr10-69288744-A-G
• rs1589439508
• NM_001358263.1:c.1A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate 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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 33 codons. Genomic position: 69343848. Lost 0.035 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.1A>G	p.Met1?	start_lost	Exon 3 of 21	ENST00000643399.2	NP_001345192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.1A>G	p.Met1?	start_lost	Exon 3 of 21		NM_001358263.1	ENSP00000494664.1

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

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
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;