5-176881147-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002115.3(HK3):​c.2698G>A​(p.Glu900Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

HK3
NM_002115.3 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66
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]
UNC5A (HGNC:12567): (unc-5 netrin receptor A) UNC5A belongs to a family of netrin-1 (MIM 601614) receptors thought to mediate the chemorepulsive effect of netrin-1 on specific axons. For more information on UNC5 proteins, see UNC5C (MIM 603610).[supplied by OMIM, Apr 2004]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HK3NM_002115.3 linkc.2698G>A p.Glu900Lys missense_variant Exon 19 of 19 ENST00000292432.10 NP_002106.2 P52790A0A024R7R1
UNC5ANM_133369.3 linkc.*1261C>T downstream_gene_variant ENST00000329542.9 NP_588610.2 Q6ZN44-1
UNC5AXM_006714928.2 linkc.*1261C>T downstream_gene_variant XP_006714991.1 H0Y8R2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HK3ENST00000292432.10 linkc.2698G>A p.Glu900Lys missense_variant Exon 19 of 19 1 NM_002115.3 ENSP00000292432.5 P52790
UNC5AENST00000329542.9 linkc.*1261C>T downstream_gene_variant 1 NM_133369.3 ENSP00000332737.4 Q6ZN44-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000480
AC:
12
AN:
249966
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135466
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000348
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1460816
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
726736
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2698G>A (p.E900K) alteration is located in exon 19 (coding exon 18) of the HK3 gene. This alteration results from a G to A substitution at nucleotide position 2698, causing the glutamic acid (E) at amino acid position 900 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.061
T
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.56
D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Benign
1.2
L
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-2.8
D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0060
D
Sift4G
Benign
0.19
T
Polyphen
0.18
B
Vest4
0.60
MutPred
0.74
Gain of ubiquitination at E900 (P = 0.0138);
MVP
0.94
MPC
0.14
ClinPred
0.25
T
GERP RS
5.2
Varity_R
0.38
gMVP
0.33

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs546596860; hg19: chr5-176308148; API