FRAS1

protein-coding

Fraser extracellular matrix complex subunit 1

Gene summary

This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

MANE transcript

NM_025074.7

Inheritance

AR, AD

ClinVar variants

P:327U:1258B:1172

Top phenotype

Fraser syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr4:78,057,323-78,544,269

External References & Databases

Ensembl (ENSG00000138759)

Transcript & Mutation Effects

hg38 • Region Span ~486.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fraser syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009046

Submitter: ClinGen

FRAS1 was first reported in relation to autosomal recessive Fraser Syndrome 1 in 2003 (McGreggot et al., PMID: 12766769). Fraser Syndrome is a rare congenital malformation typically characterized by eye anomalies (unilateral or bilateral cryptophthalmos, microphthalmos/anophthalmos), renal agenesis, bladder atresia/hypoplasia, genital anomalies (ambiguous genitalia, cryptorchidism, underdevelopment of male genitalia), and syndactyly. Fraser Syndrome can also cause multisystem anomalies, including craniofacial, cardiac, digestive, skeletal, and respiratory system abnormalities. At the time of this curation, there were no other single-gene disorders associated with this gene. There was some evidence supporting an autosomal dominant inheritance pattern for Fraser Syndrome, which has been curated separately.8 variants (nonsense, frameshift, splice site) that have been reported in 7 probands in 3 publications (PMIDs: 12766769, 16894541, 17163535) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (if applicable). The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by animal models and expression studies (PMID: 12766769). In summary, FRAS1 is definitively associated with autosomal recessive Fraser Syndrome 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen CAKUT GCEP on the meeting date 10/11/22 (SOP Version 9).

Fraser syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054737

Submitter: Natera

Fraser syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054737

Submitter: PanelApp Australia

Fraser syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009046

Submitter: Orphanet

Fraser syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054737

Submitter: Labcorp Genetics (formerly Invitae)

renal agenesis, unilateralSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019636

Submitter: Orphanet

Fraser syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054737

Submitter: G2P

Clinical Genomic Database (CGD)

Fraser syndrome 1AR

Manifestation: Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12766769; 16894541; 17163535; 18671281; 22029163

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FRAS1 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 2449

Fraser syndrome 1Total: 1058

Inborn genetic diseasesTotal: 622

FRAS1-related disorderTotal: 269

not specifiedTotal: 241

Congenital anomaly of kidney and urinary tractTotal: 7

Cryptophthalmos syndromeTotal: 5

Renal agenesisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025074.7. 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			31 clinvar	1020 clinvar	9 clinvar	1060
missense		8 clinvar	1207 clinvar	122 clinvar	20 clinvar	1357
nonsense	64 clinvar	45 clinvar	1 clinvar			110
start loss						0
frameshift	85 clinvar	45 clinvar	3 clinvar			133
splice donor/acceptor (+/-2bp)	7 clinvar	73 clinvar	16 clinvar	1 clinvar		97
Total	156	171	1258	1143	29	2757

Highest pathogenic variant AF is 0.000047101756

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025074.7	RefSeq	NP_079350.5	74	MANE Select
ENST00000512123.4	Ensembl	ENSP00000422834.2	74	MANE Select
NM_001166133.2	RefSeq	NP_001159605.1	42	Standard
ENST00000325942.11	Ensembl	ENSP00000326330.6	42	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fras1	Danio rerio	Structure: pharyngeal arch cartilage Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

fras1

Danio rerio

Structure: pharyngeal arch cartilage

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

morphogenesis of an epithelium
metanephros morphogenesis
cell communication
protein transport
embryonic limb morphogenesis

Molecular Function

extracellular matrix structural constituent
metal ion binding

Cellular Component

basement membrane
plasma membrane
integral component of membrane
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264895
Coding exons: 74
Length: 486700
Individuals with no LoFs: 124417
Homozygous LoFs: 1
Heterozygous LoFs: 287
Defined: 124705
p: 0.00116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0780	2137	2.15e+3	0.995	0.000117	26340
Missense (PolyPhen)		533	620.43	0.85908		7652
Synonymous	-0.338	846	834	1.01	0.0000479	7670
Loss of Function	5.58	104	186	0.559	0.00000959	2301

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0.00060	0.00060	rare
East Asian	0.0019	0.0018	notable
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.0013	0.0013	notable
South Asian	0.0013	0.0012	notable
Other	0.00050	0.00050	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Fraser syndrome 1 (FRASRS1) [MIM:219000]: A form of Fraser syndrome, an autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, and urogenital abnormalities including renal agenesis or hypoplasia. Additional features include abnormalities of the larynx, ear malformations, and facial abnormalities. {ECO:0000269|PubMed:12766769, ECO:0000269|PubMed:23473829}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.806
RVIS EVS: 4.65
RVIS percentile EVS: 99.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.0989

Gene Damage Prediction

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