IGFALS

protein-coding

insulin like growth factor binding protein acid labile subunit

Gene summary

The protein encoded by this gene is a serum protein that binds insulin-like growth factors, increasing their half-life and their vascular localization. Production of the encoded protein, which contains twenty leucine-rich repeats, is stimulated by growth hormone. Defects in this gene are a cause of acid-labile subunit deficiency, which maifests itself in a delayed and slow puberty. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

MANE transcript

NM_004970.3

Inheritance

ClinVar variants

P:16U:219B:73

Top phenotype

Insulin-like growth factor-binding protein, acid-labile subunit, deficiency of

gnomAD constraint

pLI —, LoF o/e 1.27

Max pathogenic AF

—

Genomic locus

chr16:1,790,413-1,794,971

External References & Databases

Ensembl (ENSG00000099769)

Transcript & Mutation Effects

hg38 • Region Span ~4.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short stature due to primary acid-labile subunit deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014420

Submitter: Orphanet

short stature due to primary acid-labile subunit deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014420

Submitter: PanelApp Australia

short stature due to primary acid-labile subunit deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014420

Submitter: Labcorp Genetics (formerly Invitae)

short stature due to primary acid-labile subunit deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014420

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Insulin-like growth factor-binding protein, acid-labile subunit, deficiency ofAR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: As growth hormone treatment has not been reported as being effective in this condition, genetic diagnosis may be beneficial in terms of pursuing optimal management

Refs: 14762184; 17726072; 21396577; 21664162; 23488611

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IGFALS variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 163

not providedTotal: 95

Short stature due to primary acid-labile subunit deficiencyTotal: 70

not specifiedTotal: 69

IGFALS-related disorderTotal: 21

Monogenic short statueTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004970.3. 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			8 clinvar	42 clinvar	6 clinvar	56
missense	2 clinvar	3 clinvar	208 clinvar	24 clinvar	1 clinvar	238
nonsense		1 clinvar	3 clinvar			4
start loss		1 clinvar				1
frameshift		9 clinvar				9
splice donor/acceptor (+/-2bp)						0
Total	2	14	219	66	7	308

Highest pathogenic variant AF is 0.000051398518

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004970.3	RefSeq	NP_004961.1	2	MANE Select
ENST00000215539.4	Ensembl	ENSP00000215539.3	2	MANE Select
NM_001146006.2	RefSeq	NP_001139478.1	2	Standard
ENST00000415638.3	Ensembl	ENSP00000416683.3	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)

Biological Process

cell adhesion
signal transduction
cellular protein metabolic process

Molecular Function

insulin-like growth factor binding

Cellular Component

extracellular region
extracellular space
nucleoplasm
extracellular matrix
insulin-like growth factor ternary complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000415638
Coding exons: 2
Length: 4559
Individuals with no LoFs: 125160
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125213
p: 0.000212

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.22	479	409	1.17	0.0000327	3959
Missense (PolyPhen)		152	131.51	1.1558		1508
Synonymous	-2.15	252	212	1.19	0.0000171	1456
Loss of Function	-0.843	14	11.0	1.27	5.67e-7	115

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.00019	0.00014	rare
European (Non-Finnish)	0.00015	0.00014	rare
South Asian	0.00040	0.00039	rare
Other	0.00052	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in protein-protein interactions that result in protein complexes, receptor-ligand binding or cell adhesion.;

Recessive Scores

pRec: 0.442

Intolerance Scores

LoFtool: 0.542
RVIS EVS: -0.88
RVIS percentile EVS: 10.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.704

Gene Damage Prediction

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