Genetic Variant HK1:c.76-10064C>G (chr10-69333763-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001358263.1(HK1):c.76-10064C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,938 control chromosomes in the GnomAD database, including 4,855 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4855 hom., cov: 31)

Consequence

HK1
NM_001358263.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.176

Publications

2 publications found

Variant links:

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]

HK1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with visual defects and brain anomalies
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
retinitis pigmentosa 79
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
non-spherocytic hemolytic anemia due to hexokinase deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Charcot-Marie-Tooth disease type 4G
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

HK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1 link	c.76-10064C>G		intron_variant	Intron 4 of 20	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3 link	c.64-10064C>G		intron_variant	Intron 1 of 17	ENST00000359426.7	NP_000179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2 link	c.76-10064C>G		intron_variant	Intron 4 of 20		NM_001358263.1	ENSP00000494664.1
HK1	ENST00000359426.7 link	c.64-10064C>G		intron_variant	Intron 1 of 17	1	NM_000188.3	ENSP00000352398.6

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33357

AN:

151820

Hom.:

4838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.402

Gnomad AMI

AF:

0.0749

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.167

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.180

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.220

AC:

33412

AN:

151938

Hom.:

4855

Cov.:

AF XY:

0.225

AC XY:

16694

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.402

AC:

16653

AN:

41382

American (AMR)

AF:

0.182

AC:

2783

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

581

AN:

3472

East Asian (EAS)

AF:

0.130

AC:

669

AN:

5156

South Asian (SAS)

AF:

0.307

AC:

1481

AN:

4822

European-Finnish (FIN)

AF:

0.235

AC:

2475

AN:

10540

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8276

AN:

68000

Other (OTH)

AF:

0.178

AC:

375

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1201

2402

3602

4803

6004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.170

Hom.:

371

Bravo

AF:

0.221

Asia WGS

AF:

0.228

AC:

793

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.7

(source)

DANN

Benign

0.52

PhyloP100

-0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over