FAM111A

protein-coding

FAM111 trypsin like peptidase A

Gene summary

The protein encoded by this gene is cell-cycle regulated, and has nuclear localization. The C-terminal half of the protein shares homology with trypsin-like peptidases and it contains a PCNA-interacting peptide (PIP) box, that is necessary for its co-localization with proliferating cell nuclear antigen (PCNA). Reduced expression of this gene resulted in DNA replication defects, consistent with the demonstrated role for this gene in Simian Virus 40 (SV40) viral replication. Mutations in this gene have been associated with Kenny-Caffey syndrome (KCS) type 2 and the more severe osteocraniostenosis (OCS, also known as Gracile Bone Dysplasia), both characterized by short stature, hypoparathyroidism, bone development abnormalities, and hypocalcemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

MANE transcript

NM_001312909.2

Inheritance

ClinVar variants

P:11U:204B:142

Top phenotype

Kenny-Caffey syndrome, type 2

gnomAD constraint

pLI —, LoF o/e 2.09

Max pathogenic AF

—

Genomic locus

chr11:59,142,748-59,155,039

External References & Databases

Ensembl (ENSG00000166801)

Transcript & Mutation Effects

hg38 • Region Span ~12.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant Kenny-Caffey syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007478

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal dominant Kenny-Caffey syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007478

Submitter: G2P

FAM111A-related skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1060172

Submitter: ClinGen

FAM111A was first reported in relation to autosomal dominant Kenney-Caffey syndrome type 2 [MIM: 127000, ORPHA: 93325, MONDO: 0007478] and autosomal dominant Gracile Bone Dysplasia/Osteocraniostenosis [MIM 602361, ORPHA:2763, MONDO:0011215] in 2013 (Unger et al, PMID 23684011). At least 16 unique variants (missense, in-frame indel, frameshift, and splicing) have been reported in humans. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is insufficient evidence of a difference in molecular mechanisms or inheritance pattern despite a few genotype:phenotype correlations that may explain the phenotypic spectrum observed from FAM111A variation. There is one case of bi-allelic variants causing disease in each entity, with no appreciable phenotype reported in either heterozygous parent. There is also a heterozygous variant (P527T) that has been reported in both disease entities. Therefore Kenney-Caffey Syndrome type 2 and Gracile Bone Dysplasia/Osteocraniostenosis have been lumped into one disease entity, “FAM111A-related skeletal dysplasia” with autosomal dominant/autosomal recessive inheritance. This disease is characterized by skeletal, ocular, endocrine, neurologic, splenic, renal, and growth anomalies, as well as facial dysmorphism, with the most frequent features being short stature, cortical thickening of the tubular bones with stenosis or obliteration of the medullary cavity and hypoparathyroidism. The reported prenatal phenotype by ultrasound examination for milder presentations includes fetal growth restriction, and for more severe presentations includes short thin tubular bones with flared metaphyses, thin ribs, small thorax, undermineralized skull, cloverleaf skull or frontal bossing, fractures, and perinatal edema (increased nuchal translucency, ascites, pleural effusion) in more severe presentations. Features detected on fetal postmortem external physical examination and Xray in severe presentations additionally include hypoplastic or absent spleen, micropenis, ventricular septal defect, and micropthalmia. As all cases in the literature were either liveborn or terminated pregnancies, the risk of fetal demise or stillbirth is unknown. This curation scored 17 variants across the following 8 publications: PMIDs 23684011, 28138333, 33263187, 33750016, 35205306, 38679371, 36916904, and 39501122. More evidence is available in the literature but the maximum score for genetic evidence (12 pts) has been reached. A recurrent variant, R569H, was reported in a total of 19 probands across 18 unrelated families. Evidence supporting this gene-disease relationship includes case-level data and variant-level experimental data in both engineered cells and patient cells. Experiments with patient variants in engineered cells has shown primarily gain-of-function of FAM111A (PMIDs 32165630, 33369867), with an additional case demonstrating a homozygous hypomorphic splice variant in patient cells (PMID 39501122). The ultimate pathogenesis of disease in patients is not currently understood. In summary, there is definitive evidence to support the relationship between FAM111A and AD/AR FAM111A-related skeletal dysplasia. 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 Prenatal Expert Panel on the meeting date April 2, 2025 (SOP version #10)

osteocraniostenosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011215

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant Kenny-Caffey syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007478

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant Kenny-Caffey syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007478

Submitter: PanelApp Australia

autosomal dominant Kenny-Caffey syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007478

Submitter: Orphanet

osteocraniostenosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011215

Submitter: Orphanet

Clinical Genomic Database (CGD)

Kenny-Caffey syndrome, type 2AD

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Ophthalmologic

Intervention: Endocrine

Rationale: Among other findings, individuals may manifest with primary hypoparathyroidism with hypocalcemia (which can be life-threatening), and awareness may allow early management

Refs: 23684011

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FAM111A variants in ClinVar

12 Conditions Cataloged

not providedTotal: 293

Inborn genetic diseasesTotal: 83

not specifiedTotal: 42

FAM111A-related disorderTotal: 29

Autosomal dominant Kenny-Caffey syndromeTotal: 18

OsteocraniostenosisTotal: 17

FAM111A-related disordersTotal: 2

Congenital heart diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001312909.2. 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			2 clinvar	70 clinvar	4 clinvar	76
missense	2 clinvar	8 clinvar	187 clinvar	40 clinvar	16 clinvar	253
nonsense		1 clinvar	5 clinvar	2 clinvar		8
start loss						0
frameshift			8 clinvar	10 clinvar		18
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	9	204	122	20	357

Highest pathogenic variant AF is 0.00001363036

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 173 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001312909.2	RefSeq	NP_001299838.1	2	MANE Select
ENST00000675163.1	Ensembl	ENSP00000501952.1	2	MANE Select
NM_001142519.3	RefSeq	NP_001135991.1	2	Standard
NM_001142520.3	RefSeq	NP_001135992.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

DNA replication
viral process
negative regulation of viral genome replication
defense response to virus

Molecular Function

protein binding

Cellular Component

chromatin
fibrillar center
nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000528737
Coding exons: 2
Length: 12292
Individuals with no LoFs: 125679
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125681
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0210	324	323	1.00	0.0000161	4101
Missense (PolyPhen)		75	76.872	0.97565		1050
Synonymous	0.413	106	112	0.950	0.00000560	1093
Loss of Function	-1.21	3	1.43	2.09	6.01e-8	19

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000098	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chromatin-associated protein required for PCNA loading on replication sites. Promotes S-phase entry and DNA synthesis (PubMed:24561620). May directly function at replication forks, explaining why Simian virus 40 (SV40) interacts with FAM111A to overcome host range restriction (PubMed:23093934). {ECO:0000269|PubMed:23093934, ECO:0000269|PubMed:24561620}.;
Disease: DISEASE: Kenny-Caffey syndrome 2 (KCS2) [MIM:127000]: A disorder characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. Clinical features include cortical thickening and medullary stenosis of the tubular bones, delayed closure of fontanels, defective dentition, small eyes with hypermetropia, and frontal bossing with a triangular face. {ECO:0000269|PubMed:23684011, ECO:0000269|PubMed:23996431, ECO:0000269|PubMed:24635597}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Gracile bone dysplasia (GCLEB) [MIM:602361]: A perinatally lethal condition characterized by narrowing of the medullary cavity of the long bones and of the skull, gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia. Most affected individuals who survive beyond the perinatal period develop hypocalcemia with low parathyroid hormone levels. {ECO:0000269|PubMed:23684011}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.239
RVIS EVS: -0.26
RVIS percentile EVS: 34.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.000122

Gene Damage Prediction

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