10-69295692-ATTTT-ATTT

Variant names:

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

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+23delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,422,050 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (10 hom.)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• 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-AT-A is Benign according to our data. Variant chr10-69295692-AT-A is described in ClinVar as Benign. ClinVar VariationId is 811676.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00186 (281/150864) while in subpopulation NFE AF = 0.00251 (170/67652). AF 95% confidence interval is 0.0022. There are 1 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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+23delT		intron	N/A	NP_001345192.1	P19367-3
	HK1	NM_001322365.2		c.168+23delT		intron	N/A	NP_001309294.1
	HK1	NM_001322364.2		c.75+23delT		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+13delT		intron	N/A	ENSP00000494664.1	P19367-3
	HK1	ENST00000464803.6	TSL:1	c.168+13delT		intron	N/A	ENSP00000496531.1	A0A2R8Y7T9
	HK1	ENST00000480047.5	TSL:1	n.379+13delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 278 AN: 150756 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.00126

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00401 AC: 858 AN: 214090 AF XY: 0.00421

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.00303

Gnomad ASJ exome AF: 0.00193

Gnomad EAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00566

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00664 AC: 8443 AN: 1271186 Hom.: 10 Cov.: 23 AF XY: 0.00631 AC XY: 4016 AN XY: 636020

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

African (AFR) AF: 0.00646 AC: 187 AN: 28932

American (AMR) AF: 0.00275 AC: 107 AN: 38846

Ashkenazi Jewish (ASJ) AF: 0.00163 AC: 38 AN: 23256

East Asian (EAS) AF: 0.000810 AC: 30 AN: 37016

South Asian (SAS) AF: 0.00358 AC: 281 AN: 78420

European-Finnish (FIN) AF: 0.00384 AC: 184 AN: 47898

Middle Eastern (MID) AF: 0.00254 AC: 13 AN: 5128

European-Non Finnish (NFE) AF: 0.00761 AC: 7301 AN: 958906

Other (OTH) AF: 0.00572 AC: 302 AN: 52784

⚠️ 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: 0.00186 AC: 281 AN: 150864 Hom.: 1 Cov.: 33 AF XY: 0.00176 AC XY: 130 AN XY: 73718

African (AFR) AF: 0.00155 AC: 64 AN: 41174

American (AMR) AF: 0.00126 AC: 19 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000778 AC: 4 AN: 5140

South Asian (SAS) AF: 0.00168 AC: 8 AN: 4772

European-Finnish (FIN) AF: 0.00126 AC: 13 AN: 10336

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00251 AC: 170 AN: 67652

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00944 Hom.: 1

Bravo AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (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; COSMIC: COSV64352549; COSMIC: COSV64352549;