FREM2

FRAS1 related extracellular matrix 2

Basic information

Region (hg38): 13:38687076-38887131

Links

ENSG00000150893 ∙ NCBI:341640 ∙ OMIM:608945 ∙ HGNC:25396 ∙ Uniprot:Q5SZK8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Fraser syndrome 1 (Definitive), mode of inheritance: AR
• Fraser syndrome 2 (Moderate), mode of inheritance: AR
• Fraser syndrome (Supportive), mode of inheritance: AR
• renal agenesis, unilateral (Supportive), mode of inheritance: AD
• Fraser syndrome 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Fraser syndrome 2; Cryptophthalmos, unilateral or bilateral, isolated	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; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal	15838507; 18203166; 18000968; 18671281; 30802441

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FREM2 gene.

• not provided (717 variants)
• Fraser syndrome 2 (361 variants)
• Inborn genetic diseases (159 variants)
• Fraser syndrome 2;Isolated cryptophthalmia (59 variants)
• not specified (53 variants)
• Isolated cryptophthalmia;Fraser syndrome 2 (41 variants)
• Fraser syndrome 1 (32 variants)
• FREM2-related condition (14 variants)
• Isolated cryptophthalmia (9 variants)
• Microcephaly (2 variants)
• Congenital anomaly of kidney and urinary tract (2 variants)
• Childhood-onset schizophrenia (1 variants)
• Congenital diaphragmatic hernia (1 variants)
• Epidermolysis bullosa simplex with nail dystrophy (1 variants)
• 8 conditions (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FREM2 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			21	232	18	271
missense		2	410	20	23	455
nonsense	10	6	3			19
start loss			1			1
frameshift	18	9				27
inframe indel						0
splice donor/acceptor (+/-2bp)		4	1			5
splice region			3	15	3	21
non coding			98	47	89	234
Total	28	21	534	299	130

Highest pathogenic variant AF is 0.0000197

Variants in FREM2

This is a list of pathogenic ClinVar variants found in the FREM2 region.

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

Position	Type	Phenotype	Significance	ClinVar
13-38687085-A-G		Fraser syndrome 2	Benign (Jun 21, 2021)
13-38687094-A-G		Fraser syndrome 2	Uncertain significance (Jan 13, 2018)
13-38687101-G-T		Fraser syndrome 2	Uncertain significance (Jan 12, 2018)
13-38687126-G-A		Fraser syndrome 2	Uncertain significance (Jan 13, 2018)
13-38687152-T-C		Fraser syndrome 2	Uncertain significance (Jan 12, 2018)
13-38687163-G-A		Fraser syndrome 2	Likely benign (Jan 13, 2018)
13-38687312-A-G		Fraser syndrome 2	Uncertain significance (Jan 13, 2018)
13-38687345-A-G		Fraser syndrome 2	Uncertain significance (Jan 13, 2018)
13-38687356-C-A			Likely benign (Oct 28, 2023)
13-38687356-C-T			Likely benign (Dec 07, 2023)
13-38687356-CG-C		Fraser syndrome 2	Pathogenic (Apr 10, 2019)
13-38687357-G-T		Inborn genetic diseases	Uncertain significance (Nov 13, 2023)
13-38687358-G-T		Inborn genetic diseases	Uncertain significance (Nov 13, 2023)
13-38687368-G-A			Likely benign (Oct 07, 2023)
13-38687374-C-T			Likely benign (Dec 23, 2022)
13-38687382-G-A		Fraser syndrome 2	Uncertain significance (Apr 10, 2022)
13-38687382-G-T			Uncertain significance (Dec 22, 2022)
13-38687383-G-C			Likely benign (May 19, 2023)
13-38687386-A-G			Likely benign (Oct 18, 2023)
13-38687396-A-G		Inborn genetic diseases	Uncertain significance (Jun 06, 2022)
13-38687409-C-T		Fraser syndrome 2 • Fraser syndrome 2;Isolated cryptophthalmia	Uncertain significance (Jul 02, 2022)
13-38687410-A-G			Likely benign (Jun 16, 2023)
13-38687425-G-A			Likely benign (Sep 22, 2023)
13-38687428-C-G		not specified • Fraser syndrome 2 • Fraser syndrome 2;Isolated cryptophthalmia	Benign/Likely benign (Jan 31, 2024)
13-38687428-C-T			Likely benign (Aug 29, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FREM2	protein_coding	protein_coding	ENST00000280481	24	198809

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.60e-11	1.00	125616	0	132	125748	0.000525

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.859	1835	1.73e+3	1.06	0.0000950	20721
Missense in Polyphen		393	459.66	0.85498		5544
Synonymous	-1.48	727	678	1.07	0.0000376	6524
Loss of Function	6.05	38	105	0.363	0.00000603	1236

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000879	0.000879
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000109	0.000109
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000689	0.000686
Middle Eastern	0.000109	0.000109
South Asian	0.000523	0.000523
Other	0.000492	0.000489

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.413
• hipred: Y
• hipred_score: 0.604
• ghis: 0.479

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.838

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Frem2
• Phenotype: pigmentation phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); reproductive system phenotype; respiratory system phenotype; embryo phenotype; skeleton phenotype; renal/urinary system phenotype; vision/eye phenotype; muscle 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); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; growth/size/body region 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); craniofacial phenotype

Zebrafish Information Network

• Gene name: frem2b
• Affected structure: blood island
• Phenotype tag: abnormal
• Phenotype quality: blistered

Gene ontology

• Biological process: eye development;morphogenesis of an epithelium;cell communication;cell adhesion;heart development;embryonic digit morphogenesis;inner ear development
• Cellular component: basement membrane;plasma membrane;integral component of membrane;extracellular exosome
• Molecular function: metal ion binding