FREM1

FRAS1 related extracellular matrix 1, the group of C-type lectin domain containing

Basic information

Region (hg38): 9:14737151-14910995

Previous symbols: [ "C9orf154" ]

Links

ENSG00000164946 ∙ NCBI:158326 ∙ OMIM:608944 ∙ HGNC:23399 ∙ Uniprot:Q5H8C1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• oculotrichoanal syndrome (Definitive), mode of inheritance: AR
• trigonocephaly 2 (Disputed Evidence), mode of inheritance: AD
• trigonocephaly 2 (Limited), mode of inheritance: AD
• oculotrichoanal syndrome (Moderate), mode of inheritance: AR
• oculotrichoanal syndrome (Supportive), mode of inheritance: AR
• isolated trigonocephaly (Supportive), mode of inheritance: AD
• renal agenesis, unilateral (Supportive), mode of inheritance: AD
• BNAR syndrome (Supportive), mode of inheritance: AR
• BNAR syndrome (Strong), mode of inheritance: AR
• oculotrichoanal syndrome (Strong), mode of inheritance: AR
• trigonocephaly 2 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Bifid nose with or without anorectal and renal anomalies; Trigonocephaly 2; Manitoba oculotrichoanal syndrome	AD/AR	General	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	Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal; Ophthalmologic; Renal	1554017; 11332973; 11822703; 17352387; 19732862; 21507892; 21931569; 23112756; 23221805

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FREM1 gene.

• not provided (496 variants)
• Oculotrichoanal syndrome (224 variants)
• Inborn genetic diseases (117 variants)
• not specified (30 variants)
• BNAR syndrome;Oculotrichoanal syndrome;Trigonocephaly 2 (23 variants)
• Oculotrichoanal syndrome;BNAR syndrome;Trigonocephaly 2 (14 variants)
• Oculotrichoanal syndrome;Trigonocephaly 2;BNAR syndrome (12 variants)
• FREM1-related condition (11 variants)
• Trigonocephaly 2;Oculotrichoanal syndrome;BNAR syndrome (7 variants)
• Trigonocephaly 2 (7 variants)
• BNAR syndrome (6 variants)
• BNAR syndrome;Trigonocephaly 2;Oculotrichoanal syndrome (6 variants)
• Trigonocephaly 2;BNAR syndrome;Oculotrichoanal syndrome (3 variants)
• Congenital diaphragmatic hernia (1 variants)
• Chronic kidney disease (1 variants)
• Congenital anomaly of kidney and urinary tract (1 variants)
• Irido-corneo-trabecular dysgenesis;Rieger anomaly (1 variants)
• Trigonocephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FREM1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			20	84	26	130
missense		2	284	20	20	326
nonsense	5	4				9
start loss	1					1
frameshift	4	2	1			7
inframe indel			3		1	4
splice donor/acceptor (+/-2bp)	1	7	1			9
splice region		1	16	9	6	32
non coding			27	32	70	129
Total	11	15	336	136	117

Highest pathogenic variant AF is 0.000138

Variants in FREM1

This is a list of pathogenic ClinVar variants found in the FREM1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-14737156-T-A		Oculotrichoanal syndrome	Uncertain significance (Jan 12, 2018)
9-14737167-G-A		Oculotrichoanal syndrome	Uncertain significance (Jan 12, 2018)
9-14737179-A-C		Oculotrichoanal syndrome	Uncertain significance (Jan 12, 2018)
9-14737194-C-G		Oculotrichoanal syndrome	Likely benign (Jan 13, 2018)
9-14737248-T-C		Oculotrichoanal syndrome	Benign (May 12, 2021)
9-14737256-AT-A		Oculotrichoanal syndrome	Uncertain significance (Jun 14, 2016)
9-14737341-C-A		Oculotrichoanal syndrome	Uncertain significance (Jan 13, 2018)
9-14737386-T-A		Oculotrichoanal syndrome	Uncertain significance (Jan 12, 2018)
9-14737408-G-A		Oculotrichoanal syndrome	Benign/Likely benign (Sep 19, 2023)
9-14737424-T-C			Uncertain significance (Jul 21, 2022)
9-14737454-T-A			Uncertain significance (Jun 09, 2022)
9-14737462-C-T		FREM1-related disorder	Benign/Likely benign (Jan 26, 2024)
9-14737471-T-C		Oculotrichoanal syndrome	Conflicting classifications of pathogenicity (Dec 21, 2023)
9-14737482-C-T		Oculotrichoanal syndrome • Oculotrichoanal syndrome;BNAR syndrome;Trigonocephaly 2	Uncertain significance (Mar 23, 2022)
9-14737490-T-C		Inborn genetic diseases	Uncertain significance (Mar 06, 2023)
9-14737505-C-T			Uncertain significance (Nov 10, 2022)
9-14737506-G-A		Oculotrichoanal syndrome;BNAR syndrome;Trigonocephaly 2	Uncertain significance (Dec 29, 2021)
9-14737508-T-G		not specified • Oculotrichoanal syndrome	Benign (Jan 31, 2024)
9-14737518-C-T			Uncertain significance (Dec 23, 2021)
9-14737528-A-G			Likely benign (Mar 22, 2023)
9-14737544-G-A		Inborn genetic diseases	Uncertain significance (Jan 09, 2024)
9-14737573-A-G		Oculotrichoanal syndrome	Uncertain significance (Mar 02, 2018)
9-14737577-T-A		Inborn genetic diseases	Uncertain significance (Dec 03, 2021)
9-14737577-T-C			Uncertain significance (Oct 22, 2023)
9-14737588-G-A		FREM1-related disorder	Likely benign (Mar 25, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FREM1	protein_coding	protein_coding	ENST00000422223	36	176330

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.57e-52	2.53e-7	124467	1	211	124679	0.000851

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-3.51	1485	1.15e+3	1.29	0.0000597	14317
Missense in Polyphen		346	286.77	1.2065		3704
Synonymous	-5.00	575	441	1.30	0.0000246	4182
Loss of Function	0.608	83	89.2	0.931	0.00000428	1126

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00244	0.00234
Ashkenazi Jewish	0.000301	0.000298
East Asian	0.000572	0.000556
Finnish	0.000704	0.000696
European (Non-Finnish)	0.000717	0.000699
Middle Eastern	0.000572	0.000556
South Asian	0.00168	0.00160
Other	0.000501	0.000495

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development. {ECO:0000250}.
• Disease: DISEASE: Bifid nose, with or without anorectal and renal anomalies (BNAR) [MIM:608980]: A disease characterized by the presence of a bifid nose usually associated with renal agenesis and anorectal malformations. A bifid nose is a congenital deformity due to failure of the paired nasal processes to fuse to a single midline organ during early gestation. {ECO:0000269|PubMed:19732862}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Manitoba oculotrichoanal syndrome (MOTA) [MIM:248450]: A rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. {ECO:0000269|PubMed:21507892, ECO:0000269|PubMed:28111185}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Trigonocephaly 2 (TRIGNO2) [MIM:614485]: A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. {ECO:0000269|PubMed:21931569}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.102

Intolerance Scores

• loftool: 0.995
• rvis_EVS: -0.63
• rvis_percentile_EVS: 17.04

Haploinsufficiency Scores

• pHI: 0.100
• ghis: 0.471

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.548

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Frem1
• Phenotype: liver/biliary system phenotype; respiratory system phenotype; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); vision/eye phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; skeleton phenotype; renal/urinary system phenotype; endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; craniofacial phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: frem1a
• Affected structure: dorsal fin
• Phenotype tag: abnormal
• Phenotype quality: has fewer parts of type

Gene ontology

• Biological process: cell communication;cell-matrix adhesion;craniofacial suture morphogenesis
• Cellular component: basement membrane;integral component of membrane
• Molecular function: carbohydrate binding;metal ion binding