NM_001358263.1:c.76-10191C>T

Variant names:

• chr10-69333636-C-T
• rs16926246
• NM_001358263.1:c.76-10191C>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.76-10191C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 151,898 control chromosomes in the GnomAD database, including 1,275 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 0.12 (1275 hom., cov: 31)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 53 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.76-10191C>T		intron_variant	Intron 4 of 20	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3	c.64-10191C>T		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	c.76-10191C>T		intron_variant	Intron 4 of 20		NM_001358263.1	ENSP00000494664.1
HK1	ENST00000359426.7	c.64-10191C>T		intron_variant	Intron 1 of 17	1	NM_000188.3	ENSP00000352398.6

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18596 AN: 151780 Hom.: 1276 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.0615

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.127

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

GnomAD4 genome AF: 0.122 AC: 18597 AN: 151898 Hom.: 1275 Cov.: 31 AF XY: 0.118 AC XY: 8753 AN XY: 74246

African (AFR) AF: 0.165 AC: 6842 AN: 41408

American (AMR) AF: 0.107 AC: 1626 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3466

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5160

South Asian (SAS) AF: 0.0716 AC: 344 AN: 4806

European-Finnish (FIN) AF: 0.0615 AC: 649 AN: 10546

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.121 AC: 8254 AN: 67958

Other (OTH) AF: 0.125 AC: 264 AN: 2108

Alfa AF: 0.122 Hom.: 576

Bravo AF: 0.130

Asia WGS AF: 0.0470 AC: 165 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.66
DANN	Benign	0.27
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16926246; hg19: chr10-71093392;