Genetic Variant HK3:p.Gly743Ser (chr5-176881954-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002115.3(HK3):c.2227G>A(p.Gly743Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,613,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

HK3
NM_002115.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05

Publications

0 publications found

Variant links:

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]

HK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

BS2

High AC in GnomAd4 at 9 AD gene.

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.2227G>A	p.Gly743Ser	missense	Exon 16 of 19	NP_002106.2	P52790

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HK3	ENST00000292432.10	TSL:1 MANE Select	c.2227G>A	p.Gly743Ser	missense	Exon 16 of 19	ENSP00000292432.5	P52790
HK3	ENST00000506834.5	TSL:1	n.1239G>A		non_coding_transcript_exon	Exon 7 of 10
HK3	ENST00000874508.1		c.2227G>A	p.Gly743Ser	missense	Exon 16 of 19	ENSP00000544567.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000956

AC:

AN:

251162

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461308

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000580

AC:

AN:

39680

South Asian (SAS)

AF:

0.000186

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1111920

Other (OTH)

AF:

0.0000497

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41458

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

PhyloP100

5.1

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.82

Sift

Benign

0.082

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.65

MutPred

0.78

Gain of disorder (P = 0.0619)

MVP

0.98

MPC

0.46

ClinPred

0.76

GERP RS

3.3

Varity_R

0.29

gMVP

0.83

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over