10-69295692-ATTTT-ATTTTT

Variant names:

• chr10-69295692-A-AT
• rs111682217
• NM_001358263.1:c.75+23dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001358263.1(HK1):​c.75+23dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,444,570 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (3 hom.)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.177
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 10-69295692-A-AT is Benign according to our data. Variant chr10-69295692-A-AT is described in ClinVar as Benign. ClinVar VariationId is 3766615.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00468 (706/150884) while in subpopulation AFR AF = 0.0137 (563/41180). AF 95% confidence interval is 0.0127. There are 5 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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+23dupT		intron	N/A	NP_001345192.1	P19367-3
	HK1	NM_001322365.2		c.168+23dupT		intron	N/A	NP_001309294.1
	HK1	NM_001322364.2		c.75+23dupT		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+12_75+13insT		intron	N/A	ENSP00000494664.1	P19367-3
	HK1	ENST00000464803.6	TSL:1	c.168+12_168+13insT		intron	N/A	ENSP00000496531.1	A0A2R8Y7T9
	HK1	ENST00000480047.5	TSL:1	n.379+12_379+13insT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 691 AN: 150776 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00359

Gnomad ASJ AF: 0.00463

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000628

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000768

Gnomad OTH AF: 0.00387

GnomAD2 exomes AF: 0.00294 AC: 629 AN: 214090 AF XY: 0.00240

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00420

Gnomad EAS exome AF: 0.000121

Gnomad FIN exome AF: 0.000888

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00802

GnomAD4 exome AF: 0.00351 AC: 4537 AN: 1293686 Hom.: 3 Cov.: 23 AF XY: 0.00325 AC XY: 2105 AN XY: 647430

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0169 AC: 499 AN: 29492

American (AMR) AF: 0.00527 AC: 213 AN: 40400

Ashkenazi Jewish (ASJ) AF: 0.00541 AC: 129 AN: 23830

East Asian (EAS) AF: 0.000187 AC: 7 AN: 37514

South Asian (SAS) AF: 0.00107 AC: 86 AN: 80182

European-Finnish (FIN) AF: 0.000490 AC: 24 AN: 48976

Middle Eastern (MID) AF: 0.0111 AC: 58 AN: 5210

European-Non Finnish (NFE) AF: 0.00333 AC: 3246 AN: 974244

Other (OTH) AF: 0.00511 AC: 275 AN: 53838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00468 AC: 706 AN: 150884 Hom.: 5 Cov.: 33 AF XY: 0.00473 AC XY: 349 AN XY: 73726

African (AFR) AF: 0.0137 AC: 563 AN: 41180

American (AMR) AF: 0.00359 AC: 54 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 16 AN: 3458

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5140

South Asian (SAS) AF: 0.000629 AC: 3 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10340

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.000769 AC: 52 AN: 67660

Other (OTH) AF: 0.00527 AC: 11 AN: 2086

Alfa AF: 0.00208 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs111682217; hg19: chr10-71055448;