10-69300854-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_033500.2(HK1):c.20A>G(p.His7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.917 in 1,569,990 control chromosomes in the GnomAD database, including 661,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 61843 hom., cov: 32)

Exomes 𝑓: 0.92 ( 599630 hom. )

Consequence

HK1
NM_033500.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.776

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 links:

RPS15AP28 (HGNC:36381): (ribosomal protein S15a pseudogene 28)

RPS15AP28 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the HK1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Trascript score misZ: 5.1348 (above the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa 79, non-spherocytic hemolytic anemia due to hexokinase deficiency, neurodevelopmental disorder with visual defects and brain anomalies, Charcot-Marie-Tooth disease type 4G.

BP4

Computational evidence support a benign effect (MetaRNN=3.5265414E-6).

BP6

Variant 10-69300854-A-G is Benign according to our data. Variant chr10-69300854-A-G is described in ClinVar as [Benign]. Clinvar id is 994062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-69300854-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1 link	c.75+5174A>G		intron_variant	Intron 4 of 20	ENST00000643399.2	NP_001345192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2 link	c.75+5174A>G		intron_variant	Intron 4 of 20		NM_001358263.1	ENSP00000494664.1		P19367-3

Frequencies

GnomAD3 genomes

AF:

0.900

AC:

136911

AN:

152042

Hom.:

61793

Cov.:

show subpopulations

Gnomad AFR

AF:

0.850

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.888

Gnomad ASJ

AF:

0.847

Gnomad EAS

AF:

0.992

Gnomad SAS

AF:

0.891

Gnomad FIN

AF:

0.951

Gnomad MID

AF:

0.861

Gnomad NFE

AF:

0.924

Gnomad OTH

AF:

0.902

GnomAD3 exomes

AF:

0.910

AC:

225378

AN:

247658

Hom.:

102784

AF XY:

0.911

AC XY:

122017

AN XY:

133998

show subpopulations

Gnomad AFR exome

AF:

0.846

Gnomad AMR exome

AF:

0.879

Gnomad ASJ exome

AF:

0.847

Gnomad EAS exome

AF:

0.991

Gnomad SAS exome

AF:

0.883

Gnomad FIN exome

AF:

0.944

Gnomad NFE exome

AF:

0.922

Gnomad OTH exome

AF:

0.907

GnomAD4 exome

AF:

0.919

AC:

1303300

AN:

1417830

Hom.:

599630

Cov.:

AF XY:

0.918

AC XY:

649805

AN XY:

707736

show subpopulations

Gnomad4 AFR exome

AF:

0.844

Gnomad4 AMR exome

AF:

0.882

Gnomad4 ASJ exome

AF:

0.847

Gnomad4 EAS exome

AF:

0.994

Gnomad4 SAS exome

AF:

0.884

Gnomad4 FIN exome

AF:

0.940

Gnomad4 NFE exome

AF:

0.924

Gnomad4 OTH exome

AF:

0.914

GnomAD4 genome

AF:

0.900

AC:

137018

AN:

152160

Hom.:

61843

Cov.:

AF XY:

0.901

AC XY:

67025

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.850

Gnomad4 AMR

AF:

0.888

Gnomad4 ASJ

AF:

0.847

Gnomad4 EAS

AF:

0.992

Gnomad4 SAS

AF:

0.890

Gnomad4 FIN

AF:

0.951

Gnomad4 NFE

AF:

0.924

Gnomad4 OTH

AF:

0.904

Alfa

AF:

0.915

Hom.:

78274

Bravo

AF:

0.894

TwinsUK

AF:

0.924

AC:

3427

ALSPAC

AF:

0.928

AC:

3577

ESP6500AA

AF:

0.848

AC:

3737

ESP6500EA

AF:

0.922

AC:

7932

ExAC

AF:

0.907

AC:

110094

Asia WGS

AF:

0.939

AC:

3263

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa 79

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemolytic anemia due to hexokinase deficiency

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder with visual defects and brain anomalies

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4G

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.6

DANN

Benign

0.48

DEOGEN2

Benign

0.0038

.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00018

LIST_S2

Benign

0.15

T;T

MetaRNN

Benign

0.0000035

T;T

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.064

Sift

Benign

0.44

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.010

B;.

Vest4

0.014

ClinPred

0.00055

GERP RS

-1.0

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over