10-69295658-T-C

Variant names:

• chr10-69295658-T-C
• rs79002951
• NM_001358263.1:c.53T>C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001358263.1(HK1):​c.53T>C​(p.Leu18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,608,170 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: HK1 NM_001358263.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.79

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]

ACMG classification

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: 5.1108 (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=0.004983008).
• BP6: Variant 10-69295658-T-C is Benign according to our data. Variant chr10-69295658-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 994196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00252 (384/152348) while in subpopulation AFR AF= 0.0089 (370/41586). AF 95% confidence interval is 0.00815. There are 2 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.53T>C	p.Leu18Pro	missense_variant	Exon 4 of 21	ENST00000643399.2	NP_001345192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.53T>C	p.Leu18Pro	missense_variant	Exon 4 of 21		NM_001358263.1	ENSP00000494664.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152230 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00897

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000680 AC: 171 AN: 251370 Hom.: 3 AF XY: 0.000397 AC XY: 54 AN XY: 135864

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000276 AC: 402 AN: 1455822 Hom.: 3 Cov.: 28 AF XY: 0.000224 AC XY: 162 AN XY: 724730

Gnomad4 AFR exome AF: 0.00867

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000542

Gnomad4 OTH exome AF: 0.000465

GnomAD4 genome AF: 0.00252 AC: 384 AN: 152348 Hom.: 2 Cov.: 34 AF XY: 0.00232 AC XY: 173 AN XY: 74504

Gnomad4 AFR AF: 0.00890

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000544 Hom.: 0

Bravo AF: 0.00275

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000824 AC: 100

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Charcot-Marie-Tooth disease type 4G;C3150343:Hemolytic anemia due to hexokinase deficiency;C4479526:Retinitis pigmentosa 79;C5231404:Neurodevelopmental disorder with visual defects and brain anomalies Benign:1

Oct 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HK1-related disorder Benign:1

Feb 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.0090
DANN	Benign	0.41
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.29	.;T;T;T;T;.
MetaRNN	Benign	0.0050	T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.76	.;N;.;.;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.026	.;D;.;.;.;.
Sift4G	Benign	0.28	.;T;T;.;.;.
Polyphen		0.34	B;.;B;.;.;B
Vest4		0.17
MVP		0.43
ClinPred		0.0049	T
GERP RS		-7.3
gMVP		0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs79002951; hg19: chr10-71055414;