5-176881333-C-A

Variant names:

• chr5-176881333-C-A
• rs1322592654
• NM_002115.3:c.2596G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002115.3(HK3):​c.2596G>T​(p.Val866Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V866M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HK3 NM_002115.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

Genes affected

HK3 (HGNC:4925): (hexokinase 3) Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes hexokinase 3. Similar to hexokinases 1 and 2, this allosteric enzyme is inhibited by its product glucose-6-phosphate. [provided by RefSeq, Apr 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002115.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK3	NM_002115.3	MANE Select	c.2596G>T	p.Val866Leu	missense	Exon 18 of 19	NP_002106.2	P52790

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK3	ENST00000292432.10	TSL:1 MANE Select	c.2596G>T	p.Val866Leu	missense	Exon 18 of 19	ENSP00000292432.5	P52790
	HK3	ENST00000506834.5	TSL:1	n.1608G>T		non_coding_transcript_exon	Exon 9 of 10
	HK3	ENST00000874508.1		c.2596G>T	p.Val866Leu	missense	Exon 18 of 19	ENSP00000544567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461672 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.74		Gain of loop (P = 0.2045)
MVP		0.99
MPC		0.54
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.64
gMVP		0.43
Mutation Taster		=34/66	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: rs1322592654; hg19: chr5-176308334;