10-69295703-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001358263.1(HK1):​c.75+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,446,312 control chromosomes in the GnomAD database, including 361,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38065 hom., cov: 31)
  • Exomes 𝑓: 0.71 (323493 hom.)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: Labcorp Genetics (formerly Invitae), Orphanet, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-69295703-T-C is Benign according to our data. Variant chr10-69295703-T-C is described in ClinVar as Benign. ClinVar VariationId is 1285347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

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>C		intron	N/A	NP_001345192.1	P19367-3
	HK1	NM_001322365.2		c.168+23T>C		intron	N/A	NP_001309294.1
	HK1	NM_001322364.2		c.75+23T>C		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>C		intron	N/A	ENSP00000494664.1	P19367-3
	HK1	ENST00000464803.6	TSL:1	c.168+23T>C		intron	N/A	ENSP00000496531.1	A0A2R8Y7T9
	HK1	ENST00000480047.5	TSL:1	n.379+23T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107123 AN: 151612 Hom.: 38046 Cov.: 31

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.708

GnomAD2 exomes AF: 0.698 AC: 169689 AN: 243094 AF XY: 0.704

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.710

Gnomad EAS exome AF: 0.830

Gnomad FIN exome AF: 0.722

Gnomad NFE exome AF: 0.731

Gnomad OTH exome AF: 0.694

GnomAD4 exome AF: 0.709 AC: 918131 AN: 1294584 Hom.: 323493 Cov.: 21 AF XY: 0.711 AC XY: 463606 AN XY: 652334

African (AFR) AF: 0.651 AC: 19739 AN: 30316

American (AMR) AF: 0.537 AC: 23720 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 17564 AN: 24946

East Asian (EAS) AF: 0.850 AC: 32626 AN: 38396

South Asian (SAS) AF: 0.696 AC: 57499 AN: 82652

European-Finnish (FIN) AF: 0.722 AC: 37640 AN: 52152

Middle Eastern (MID) AF: 0.641 AC: 3486 AN: 5438

European-Non Finnish (NFE) AF: 0.715 AC: 687090 AN: 961550

Other (OTH) AF: 0.706 AC: 38767 AN: 54924

GnomAD4 genome AF: 0.706 AC: 107180 AN: 151728 Hom.: 38065 Cov.: 31 AF XY: 0.702 AC XY: 52043 AN XY: 74122

African (AFR) AF: 0.665 AC: 27519 AN: 41378

American (AMR) AF: 0.608 AC: 9268 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2492 AN: 3470

East Asian (EAS) AF: 0.839 AC: 4321 AN: 5148

South Asian (SAS) AF: 0.718 AC: 3447 AN: 4800

European-Finnish (FIN) AF: 0.720 AC: 7538 AN: 10476

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.740 AC: 50246 AN: 67898

Other (OTH) AF: 0.704 AC: 1482 AN: 2104

Alfa AF: 0.679 Hom.: 13351

Bravo AF: 0.692

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease type 4G (1)
-	-	1	Hemolytic anemia due to hexokinase deficiency (1)
-	-	1	Neurodevelopmental disorder with visual defects and brain anomalies (1)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa 79 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.88
PhyloP100		-0.70
Mutation Taster		=11/89	disease causing (long InDel)

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; COSMIC: COSV64356366; COSMIC: COSV64356366;