NM_001358263.1:c.28-2501C>T

Variant names:

• chr10-69293132-C-T
• rs10823333
• NM_001358263.1:c.28-2501C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001358263.1(HK1):​c.28-2501C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,098 control chromosomes in the GnomAD database, including 3,498 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 0.21 (3498 hom., cov: 32)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.608
• Publications: 4 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.28-2501C>T		intron_variant	Intron 3 of 20	ENST00000643399.2	NP_001345192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.28-2501C>T		intron_variant	Intron 3 of 20		NM_001358263.1	ENSP00000494664.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31897 AN: 151980 Hom.: 3490 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0762

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.186

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

GnomAD4 genome AF: 0.210 AC: 31925 AN: 152098 Hom.: 3498 Cov.: 32 AF XY: 0.212 AC XY: 15774 AN XY: 74362

African (AFR) AF: 0.258 AC: 10711 AN: 41462

American (AMR) AF: 0.187 AC: 2853 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 560 AN: 3464

East Asian (EAS) AF: 0.0756 AC: 392 AN: 5184

South Asian (SAS) AF: 0.260 AC: 1256 AN: 4828

European-Finnish (FIN) AF: 0.238 AC: 2515 AN: 10584

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12999 AN: 67982

Other (OTH) AF: 0.186 AC: 392 AN: 2112

Alfa AF: 0.192 Hom.: 4899

Bravo AF: 0.205

Asia WGS AF: 0.177 AC: 618 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	0.75
DANN	Benign	0.37
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10823333; hg19: chr10-71052888;