GeneBe

FREM2

protein-coding

FRAS1 related extracellular matrix 2

Gene summary

This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The encoded protein localizes to the basement membrane, forming a ternary complex that plays a role in epidermal-dermal interactions. This protein is important for the integrity of skin and renal epithelia. Mutations in this gene are associated with Fraser syndrome. [provided by RefSeq, Apr 2014]

MANE transcript

NM_207361.6

Inheritance

AR, AD

ClinVar variants

P:141U:983B:967

Top phenotype

Fraser syndrome 2; Cryptophthalmos, unilateral or bilateral, isolated

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr13:38,687,077-38,887,131

External References & Databases

Ensembl (ENSG00000150893)NCBI Gene (341640)OMIM (608945)HGNC:25396GenCCUniProt (Q5SZK8)AlphaFoldClinVar (FREM2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~200.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fraser syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054738

Submitter: PanelApp Australia

Fraser syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009046

Submitter: Orphanet

renal agenesis, unilateralSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019636

Submitter: Orphanet

Fraser syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054737

Submitter: Labcorp Genetics (formerly Invitae)

Fraser syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054738

Submitter: Ambry Genetics

Fraser syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054738

Submitter: G2P

Fraser syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054738

Submitter: Natera

Clinical Genomic Database (CGD)

Fraser syndrome 2; Cryptophthalmos, unilateral or bilateral, isolatedAR

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: 15838507; 18203166; 18000968; 18671281; 30802441Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FREM2 variants in ClinVar

23 Conditions Cataloged
not providedTotal: 1549
Fraser syndrome 2Total: 695
Isolated cryptophthalmiaTotal: 536
Inborn genetic diseasesTotal: 503
FREM2-related disorderTotal: 171
not specifiedTotal: 110
Fraser syndrome 1Total: 16
FREM2-related disordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_207361.6. 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.

EffectPLPVUSLBBSum
synonymous
16
clinvar
862
clinvar
6
clinvar
 884
missense
1
clinvar
3
clinvar
959
clinvar
85
clinvar
14
clinvar
 1062
nonsense
30
clinvar
20
clinvar
3
clinvar
 53
start loss
1
clinvar
 1
frameshift
49
clinvar
27
clinvar
2
clinvar
 78
splice donor/acceptor (+/-2bp)
1
clinvar
10
clinvar
2
clinvar
 13
Total8160983947202091

Highest pathogenic variant AF is 0.000055833207

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_207361.6RefSeqNP_997244.424MANE Select
ENST00000280481.9EnsemblENSP00000280481.724MANE Select
ENST00001131734.1EnsemblENSP00000804384.124Standard
XM_017020554.2RefSeqXP_016876043.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
frem2bDanio rerio

Structure: blood island

Quality: blistered

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • eye development
  • morphogenesis of an epithelium
  • cell communication
  • cell adhesion
  • heart development

Molecular Function

  • metal ion binding

Cellular Component

  • basement membrane
  • plasma membrane
  • integral component of membrane
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000280481
Coding exons
24
Length
198809
Individuals with no LoFs
125616
Homozygous LoFs
0
Heterozygous LoFs
132
Defined
125748
p
0.000525
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.85918351.73e+31.060.000095020721
Missense (PolyPhen)393459.660.854985544
Synonymous-1.487276781.070.00003766524
Loss of Function6.05381050.3630.000006031236

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.000690.00069rare
Ashkenazi Jewish0.000300.00030rare
East Asian0.000110.00011rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000690.00069rare
South Asian0.000520.00052rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Extracellular matrix protein required for maintenance of the integrity of the skin epithelium and for maintenance of renal epithelia. May be required for epidermal adhesion. {ECO:0000269|PubMed:15838507}.;
Disease
DISEASE: Fraser syndrome 2 (FRASRS2) [MIM:617666]: 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:15838507}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.112

Intolerance Scores

LoFtool
0.708
RVIS EVS
-0.63
RVIS percentile EVS
16.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.838

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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