rs6480404

Variant names:

• chr10-69349650-T-C
• rs6480404
• NM_001358263.1:c.238+5661T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001358263.1(HK1):​c.238+5661T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,002 control chromosomes in the GnomAD database, including 17,600 homozygotes. 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: 𝑓 0.46 (17600 hom., cov: 32)
• Consequence: HK1 NM_001358263.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 79

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

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HK1	NM_001358263.1	c.238+5661T>C		intron_variant	Intron 5 of 20	ENST00000643399.2	NP_001345192.1
HK1	NM_000188.3	c.226+5661T>C		intron_variant	Intron 2 of 17	ENST00000359426.7	NP_000179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HK1	ENST00000643399.2	c.238+5661T>C		intron_variant	Intron 5 of 20		NM_001358263.1	ENSP00000494664.1
HK1	ENST00000359426.7	c.226+5661T>C		intron_variant	Intron 2 of 17	1	NM_000188.3	ENSP00000352398.6

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70583 AN: 151884 Hom.: 17571 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.396

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.465 AC: 70658 AN: 152002 Hom.: 17600 Cov.: 32 AF XY: 0.469 AC XY: 34876 AN XY: 74300

African (AFR) AF: 0.632 AC: 26206 AN: 41440

American (AMR) AF: 0.345 AC: 5269 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1343 AN: 3468

East Asian (EAS) AF: 0.265 AC: 1368 AN: 5156

South Asian (SAS) AF: 0.546 AC: 2636 AN: 4824

European-Finnish (FIN) AF: 0.527 AC: 5569 AN: 10570

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 27008 AN: 67952

Other (OTH) AF: 0.398 AC: 840 AN: 2108

Alfa AF: 0.447 Hom.: 1962

Bravo AF: 0.454

Asia WGS AF: 0.427 AC: 1485 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.85
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6480404; hg19: chr10-71109406;