FLAD1

protein-coding

flavin adenine dinucleotide synthetase 1

Gene summary

This gene encodes the enzyme that catalyzes adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

MANE transcript

NM_025207.5

Inheritance

ClinVar variants

P:32U:163B:110

Top phenotype

Lipid storage myopathy due to FLAD1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr1:154,983,338-154,993,111

External References & Databases

Ensembl (ENSG00000160688)

Transcript & Mutation Effects

hg38 • Region Span ~9.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopathy with abnormal lipid metabolismMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009703

Submitter: Ambry Genetics

myopathy with abnormal lipid metabolismDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009703

Submitter: G2P

myopathy with abnormal lipid metabolismDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009703

Submitter: ClinGen

FLAD1 was first reported in relation to autosomal recessive myopathy with abnormal lipid metabolism in 2014 (Taylor RW, et al., 2014; PMID: 25058219). Twelve variants (including missense, in-frame deletions, nonsense, splicing, and frameshift) have been reported in 13 probands, and three additional family members, in seven publications (PMIDs: 30061063, 30982706, 25058219, 30311138, 27259049, 31392824, 30427553). This gene-disease association is also supported by experimental evidence including its biochemical function in catalysis of FMN into FAD (PMID: 16643857), which is altered in patient cells (PMID: 27259049), as well as an expression pattern consistent with disease (PMID: 20060505), and a C. elegans model (PMID: 22306247). In summary, FLAD1 is definitively associated with autosomal recessive myopathy with abnormal lipid metabolism. This classification was approved by the ClinGen FAO GCEP 12/16/2020 (SOP Version [7]). This gene-disease pair was originally evaluated by the FAO GCEP on 06/12/2018. It was reevaluated on 12/15/2020. Additional genetic evidence was included from new publications (PMIDs: 30061063, 30982706, 30311138, 31392824, 30427553). As a result of this reevaluation, the classification was upgraded from moderate to definitive.

myopathy with abnormal lipid metabolismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009703

Submitter: Labcorp Genetics (formerly Invitae)

myopathy with abnormal lipid metabolismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009703

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Lipid storage myopathy due to FLAD1 deficiencyAR

Manifestation: Biochemical; Cardiovascular; Neurologic

Intervention: Biochemical; Cardiovascular

Rationale: Individuals have shown clinical improvement with dietary management (riboflavin); The condition has been described with cardiomyopathy, and awareness may allow prompt diagnosis and management (eg, with medical management and ICD)

Refs: 25058219; 27259049

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FLAD1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 290

Inborn genetic diseasesTotal: 80

not specifiedTotal: 22

Myopathy with abnormal lipid metabolismTotal: 20

FLAD1-related disorderTotal: 15

Multiple acyl-CoA dehydrogenase deficiencyTotal: 10

FLAD1-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025207.5. 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			1 clinvar	94 clinvar	1 clinvar	96
missense		3 clinvar	158 clinvar	15 clinvar		176
nonsense	4 clinvar	4 clinvar	1 clinvar			9
start loss						0
frameshift	12 clinvar	5 clinvar	1 clinvar			18
splice donor/acceptor (+/-2bp)		4 clinvar	2 clinvar			6
Total	16	16	163	109	1	305

Highest pathogenic variant AF is 0.000057004912

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025207.5	RefSeq	NP_079483.3	7	MANE Select
ENST00000292180.8	Ensembl	ENSP00000292180.3	7	MANE Select
NM_001184891.2	RefSeq	NP_001171820.1	6	Standard
NM_001184892.2	RefSeq	NP_001171821.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Riboflavin metabolism - Homo sapiens (human)
Riboflavin Metabolism
Selenium Micronutrient Network
Folate Metabolism
Metabolism

Biological Process

FAD biosynthetic process
riboflavin metabolic process

Molecular Function

FMN adenylyltransferase activity
protein binding
ATP binding

Cellular Component

mitochondrial matrix
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292180
Coding exons: 7
Length: 9774
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.581	306	336	0.911	0.0000190	3728
Missense (PolyPhen)		92	103.66	0.88755		1144
Synonymous	1.72	111	137	0.812	0.00000702	1273
Loss of Function	3.07	8	24.4	0.328	0.00000131	271

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme. {ECO:0000269|PubMed:16643857, ECO:0000269|PubMed:27259049}.;
Disease: DISEASE: Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency (LSMFLAD) [MIM:255100]: An autosomal recessive, inborn error of metabolism characterized by variable mitochondrial dysfunction. Clinical features range from severe cardiac and respiratory insufficiency with onset in infancy and resulting in early death, to mild muscle weakness with onset in adulthood. Some patients show significant improvement with riboflavin treatment. Analysis of skeletal muscle show multiple mitochondrial respiratory chain deficiency and a lipid storage myopathy in most patients. {ECO:0000269|PubMed:27259049}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.232

Intolerance Scores

LoFtool: 0.0672
RVIS EVS: -1.04
RVIS percentile EVS: 7.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
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	Medium
Cancer	Medium	Medium	Medium