10-69295703-T-G

Variant names:

• chr10-69295703-T-G
• rs4746837
• NM_001358263.1:c.75+23T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001358263.1(HK1):​c.75+23T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.701
• Publications: 5 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 79

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• non-spherocytic hemolytic anemia due to hexokinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 4G

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358263.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	NM_001358263.1	MANE Plus Clinical	c.75+23T>G		intron	N/A	NP_001345192.1	P19367-3
	HK1	NM_001322365.2		c.168+23T>G		intron	N/A	NP_001309294.1
	HK1	NM_001322364.2		c.75+23T>G		intron	N/A	NP_001309293.1	P19367-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000643399.2	MANE Plus Clinical	c.75+23T>G		intron	N/A	ENSP00000494664.1	P19367-3
	HK1	ENST00000464803.6	TSL:1	c.168+23T>G		intron	N/A	ENSP00000496531.1	A0A2R8Y7T9
	HK1	ENST00000480047.5	TSL:1	n.379+23T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1298736 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 654224

African (AFR) AF: 0.00 AC: 0 AN: 30418

American (AMR) AF: 0.00 AC: 0 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24986

East Asian (EAS) AF: 0.00 AC: 0 AN: 38404

South Asian (SAS) AF: 0.00 AC: 0 AN: 82708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 965304

Other (OTH) AF: 0.00 AC: 0 AN: 55056

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.4
DANN	Benign	0.82
PhyloP100		-0.70

Splicing

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

Other links and lift over

dbSNP: rs4746837; hg19: chr10-71055459;