PFKM

protein-coding

phosphofructokinase, muscle, the group of Protein phosphatase 1 regulatory subunits|MicroRNA protein coding host genes

Gene summary

Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

Previous symbols:

PFKX

MANE transcript

NM_000289.6

Inheritance

ClinVar variants

P:166U:252B:339

Top phenotype

Glycogen storage disease VII

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr12:48,105,139-48,146,404

External References & Databases

Ensembl (ENSG00000152556)

Transcript & Mutation Effects

hg38 • Region Span ~41.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease VIISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009295

Submitter: Orphanet

glycogen storage disease VIIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009295

Submitter: Natera

glycogen storage disease VIIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009295

Submitter: Ambry Genetics

glycogen storage disease VIISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009295

Submitter: Genomics England PanelApp

glycogen storage disease VIISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009295

Submitter: PanelApp Australia

glycogen storage disease VIISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009295

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Glycogen storage disease VIIAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Hematologic; Musculoskeletal; Ophthalmologic; Renal

Intervention: Cardiovascular; Musculoskeletal; Renal

Rationale: There is a wide range of types and severity, but avoidance of excessive exercise may be beneficial in order to avoid renal sequale; Surveillance for cardiovascular complications (eg, cardiac hypertrophy) may allow early detection and treatment

Refs: 14339001; 4228297; 4228753; 4258222; 6444532; 6444721; 6943439; 6220601; 2945125; 2960695; 2140573; 1533013; 8444874; 8037209; 7513946; 7550225; 7479776; 8889589; 9389749; 22133655; 22364848

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PFKM variants in ClinVar

9 Conditions Cataloged

Glycogen storage disease, type VIITotal: 956

not providedTotal: 119

Inborn genetic diseasesTotal: 84

not specifiedTotal: 46

PFKM-related disorderTotal: 24

Glycogen storage diseaseTotal: 2

Peroxisomal biogenesis disorder 3bTotal: 1

RhabdomyolysisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000289.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	330 clinvar		337
missense	2 clinvar	7 clinvar	240 clinvar	8 clinvar	1 clinvar	258
nonsense	12 clinvar	21 clinvar	1 clinvar			34
start loss						0
frameshift	43 clinvar	42 clinvar	2 clinvar			87
splice donor/acceptor (+/-2bp)	4 clinvar	35 clinvar	2 clinvar			41
Total	61	105	252	338	1	757

Highest pathogenic variant AF is 0.00007282125

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 207 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000289.6	RefSeq	NP_000280.1	22	MANE Select
ENST00000359794.11	Ensembl	ENSP00000352842.5	22	MANE Select
NM_001166686.2	RefSeq	NP_001160158.1	24	Standard
NM_001166687.2	RefSeq	NP_001160159.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycolysis / Gluconeogenesis - Homo sapiens (human)
Fructose and mannose metabolism - Homo sapiens (human)
Central carbon metabolism in cancer - Homo sapiens (human)
RNA degradation - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)

Biological Process

glycogen catabolic process
fructose 6-phosphate metabolic process
glucose catabolic process
glycolytic process
fructose 1,6-bisphosphate metabolic process

Molecular Function

6-phosphofructokinase activity
protein binding
ATP binding
protein C-terminus binding
AMP binding

Cellular Component

nucleus
cytosol
6-phosphofructokinase complex
apical plasma membrane
sperm principal piece

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340802
Coding exons: 24
Length: 41266
Individuals with no LoFs: 125612
Homozygous LoFs: 0
Heterozygous LoFs: 136
Defined: 125748
p: 0.000541

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.36	334	479	0.697	0.0000285	5598
Missense (PolyPhen)		107	190.53	0.56158		2254
Synonymous	1.14	153	172	0.890	0.00000999	1673
Loss of Function	1.71	34	46.6	0.730	0.00000273	514

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.0047	0.0047	notable
East Asian	0.00043	0.00044	rare
Finnish	0.00065	0.00065	rare
European (Non-Finnish)	0.00043	0.00041	rare
South Asian	0.00020	0.00020	rare
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.;
Disease: DISEASE: Glycogen storage disease 7 (GSD7) [MIM:232800]: A metabolic disorder characterized by exercise intolerance with associated nausea and vomiting, muscle cramping, exertional myopathy and compensated hemolysis. Short bursts of intense activity are particularly difficult. Severe muscle cramps and myoglobinuria develop after vigorous exercise. {ECO:0000269|PubMed:22133655, ECO:0000269|PubMed:24427140, ECO:0000269|PubMed:7513946, ECO:0000269|PubMed:7825568, ECO:0000269|PubMed:8889589}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.784

Intolerance Scores

LoFtool: 0.291
RVIS EVS: -0.46
RVIS percentile EVS: 23.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	High	Medium	High