10-69300854-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001358263.1(HK1):c.75+5174A>G variant causes a intron 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. 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_001358263.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.776

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• 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/exons	MANE	UniProt
HK1	NM_001358263.1	c.75+5174A>G		intron_variant		ENST00000643399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HK1	ENST00000643399.2	c.75+5174A>G		intron_variant			NM_001358263.1
RPS15AP28	ENST00000435088.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.900 AC: 136911 AN: 152042 Hom.: 61793 Cov.: 32

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

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.: 23 AF XY: 0.918 AC XY: 649805 AN XY: 707736

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.: 32 AF XY: 0.901 AC XY: 67025 AN XY: 74390

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Retinitis pigmentosa 79 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Hemolytic anemia due to hexokinase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Neurodevelopmental disorder with visual defects and brain anomalies Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Charcot-Marie-Tooth disease type 4G Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.6
Dann	Benign	0.48
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00018	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0000035	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
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	T
GERP RS		-1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs906220; hg19: chr10-71060610;