Genetic Variant HK1:c.76-3670T>C (chr10-69340157-T-C) – 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.76-3670T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 152,076 control chromosomes in the GnomAD database, including 22,901 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 0.54 ( 22901 hom., cov: 33)

Consequence

HK1
NM_001358263.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.189

Publications

39 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=-0.94).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1 link	c.76-3670T>C		intron_variant	Intron 4 of 20	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3 link	c.64-3670T>C		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.76-3670T>C		intron_variant	Intron 4 of 20		NM_001358263.1	ENSP00000494664.1
HK1	ENST00000359426.7 link	c.64-3670T>C		intron_variant	Intron 1 of 17	1	NM_000188.3	ENSP00000352398.6

Frequencies

GnomAD3 genomes

AF:

0.537

AC:

81632

AN:

151958

Hom.:

22873

Cov.:

show subpopulations

Gnomad AFR

AF:

0.667

Gnomad AMI

AF:

0.481

Gnomad AMR

AF:

0.432

Gnomad ASJ

AF:

0.442

Gnomad EAS

AF:

0.264

Gnomad SAS

AF:

0.558

Gnomad FIN

AF:

0.581

Gnomad MID

AF:

0.376

Gnomad NFE

AF:

0.503

Gnomad OTH

AF:

0.481

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

GnomAD4 genome

AF:

0.537

AC:

81707

AN:

152076

Hom.:

22901

Cov.:

AF XY:

0.538

AC XY:

40017

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.667

AC:

27659

AN:

41476

American (AMR)

AF:

0.431

AC:

6589

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.442

AC:

1533

AN:

3470

East Asian (EAS)

AF:

0.263

AC:

1359

AN:

5174

South Asian (SAS)

AF:

0.559

AC:

2693

AN:

4820

European-Finnish (FIN)

AF:

0.581

AC:

6130

AN:

10556

Middle Eastern (MID)

AF:

0.366

AC:

107

AN:

292

European-Non Finnish (NFE)

AF:

0.503

AC:

34181

AN:

67990

Other (OTH)

AF:

0.482

AC:

1017

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1902

3804

5705

7607

9509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.506

Hom.:

74637

Bravo

AF:

0.527

Asia WGS

AF:

0.439

AC:

1526

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

3.3

(source)

DANN

Benign

0.40

PhyloP100

-0.19

Mutation Taster

=98/2

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

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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