10-69382664-G-A

Variant names:

• chr10-69382664-G-A
• rs748235
• NM_001358263.1:c.1455G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000188.3(HK1):​c.1443G>A​(p.Lys481Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,684 control chromosomes in the GnomAD database, including 505,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49185 hom., cov: 32)
  • Exomes 𝑓: 0.79 (455844 hom.)
• Consequence: HK1 NM_000188.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.894
• Publications: 29 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-69382664-G-A is Benign according to our data. Variant chr10-69382664-G-A is described in ClinVar as Benign. ClinVar VariationId is 255483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.894 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000188.3. 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.1455G>A	p.Lys485Lys	synonymous	Exon 13 of 21	NP_001345192.1	P19367-3
	HK1	NM_000188.3	MANE Select	c.1443G>A	p.Lys481Lys	synonymous	Exon 10 of 18	NP_000179.2	P19367-1
	HK1	NM_001322365.2		c.1548G>A	p.Lys516Lys	synonymous	Exon 15 of 23	NP_001309294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HK1	ENST00000643399.2	MANE Plus Clinical	c.1455G>A	p.Lys485Lys	synonymous	Exon 13 of 21	ENSP00000494664.1	P19367-3
	HK1	ENST00000359426.7	TSL:1 MANE Select	c.1443G>A	p.Lys481Lys	synonymous	Exon 10 of 18	ENSP00000352398.6	P19367-1
	HK1	ENST00000934397.1		c.1443G>A	p.Lys481Lys	synonymous	Exon 10 of 19	ENSP00000604456.1

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121654 AN: 152012 Hom.: 49144 Cov.: 32

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.902

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.805

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.788

GnomAD2 exomes AF: 0.772 AC: 193253 AN: 250250 AF XY: 0.784

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.834

Gnomad EAS exome AF: 0.681

Gnomad FIN exome AF: 0.799

Gnomad NFE exome AF: 0.790

Gnomad OTH exome AF: 0.763

GnomAD4 exome AF: 0.787 AC: 1150645 AN: 1461554 Hom.: 455844 Cov.: 67 AF XY: 0.791 AC XY: 575295 AN XY: 727088

African (AFR) AF: 0.891 AC: 29826 AN: 33480

American (AMR) AF: 0.582 AC: 25964 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 21757 AN: 26092

East Asian (EAS) AF: 0.581 AC: 23056 AN: 39694

South Asian (SAS) AF: 0.890 AC: 76721 AN: 86214

European-Finnish (FIN) AF: 0.795 AC: 42474 AN: 53408

Middle Eastern (MID) AF: 0.829 AC: 4779 AN: 5768

European-Non Finnish (NFE) AF: 0.790 AC: 877987 AN: 1111894

Other (OTH) AF: 0.796 AC: 48081 AN: 60384

GnomAD4 genome AF: 0.800 AC: 121755 AN: 152130 Hom.: 49185 Cov.: 32 AF XY: 0.798 AC XY: 59392 AN XY: 74382

African (AFR) AF: 0.880 AC: 36511 AN: 41512

American (AMR) AF: 0.663 AC: 10131 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 2897 AN: 3472

East Asian (EAS) AF: 0.647 AC: 3325 AN: 5140

South Asian (SAS) AF: 0.884 AC: 4264 AN: 4822

European-Finnish (FIN) AF: 0.805 AC: 8531 AN: 10596

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.785 AC: 53366 AN: 67978

Other (OTH) AF: 0.791 AC: 1670 AN: 2112

Alfa AF: 0.789 Hom.: 151717

Bravo AF: 0.791

Asia WGS AF: 0.780 AC: 2712 AN: 3478

EpiCase AF: 0.788

EpiControl AF: 0.795

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 79 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		-0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs748235; hg19: chr10-71142420; COSMIC: COSV53863345;