CADM3

protein-coding

cell adhesion molecule 3, the group of V-set domain containing|C2-set domain containing|Nectins and nectin-like molecules

Gene summary

The protein encoded by this gene is a calcium-independent cell-cell adhesion protein that can form homodimers or heterodimers with other nectin proteins. The encoded protein has both homophilic and heterophilic cell-cell adhesion activity. This gene is reported to be a tumor suppressor gene. [provided by RefSeq, Oct 2016]

Previous symbols:

IGSF4B

MANE transcript

NM_001127173.3

Inheritance

ClinVar variants

P:1U:69B:13

Top phenotype

Charcot-Marie-Tooth disease, axonal, type 2FF

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr1:159,171,609-159,203,313

External References & Databases

Ensembl (ENSG00000162706)

Transcript & Mutation Effects

hg38 • Region Span ~31.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease, axonal, type 2FFMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030433

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease, axonal, type 2FFSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030433

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease, axonal, type 2FFMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030433

Submitter: ClinGen

CADM3: autosomal dominant axonal Charcot-Marie-Tooth disease Evidence Summary: Cell adhesion molecule 3, CADM3, was initially shown to segregate with clinical features of autosomal dominant, axonal type Charcot-Marie-Tooth (CMT) in three unrelated families, including one confirmed de novo case, (Rebelo et al., PMID: 33889941). Clinical features of CMT axonal type include distal muscle weakness and atrophy with significant upper limb involvement, sensory loss, and foot and hand deformities, (Yalcouye et al., PMID: 38074074, Rebelo et al., PMID: 33889941). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Two missense variants have been reported in 6 families. CADM3, expressed in axons, interacts with CADM4, expressed by myelinating Schwann cells, to mediate the structural organization of myelinated fibers. Stochastic optical reconstruction microscopy imaging revealed decreased co-localization of the mutant CADM3 with CADM4 at intercellular contact sites (PMID: 33889941). Mice carrying the corresponding human mutation (Cadm3Y170C) showed reduced expression of the mutant protein in axons. Cadm3Y170C mice showed abnormal axonal organization. In summary, there is MODERATE evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Charcot-Marie-Tooth Expert Panel on 02-05-26 (SOP Version 11). Gene-Disease Validity Standard Operating Procedures, (SOP)-SOP 11

Charcot-Marie-Tooth disease, axonal, type 2FFLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030433

Submitter: Illumina

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, axonal, type 2FFAD

Manifestation: Neurologic

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: 33889941

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CADM3 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 60

not providedTotal: 16

not specifiedTotal: 12

Charcot-Marie-Tooth disease, axonal, type 2FFTotal: 6

CADM3-related conditionTotal: 5

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001127173.3. 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	10 clinvar		12
missense		1 clinvar	65 clinvar	3 clinvar		69
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	1	69	13	0	83

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001127173.3	RefSeq	NP_001120645.1	9	MANE Select
ENST00000368125.9	Ensembl	ENSP00000357107.4	9	MANE Select
NM_001346510.2	RefSeq	NP_001333439.1	9	Standard
NM_021189.5	RefSeq	NP_067012.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Splicing factor NOVA regulated synaptic proteins
Cell-cell junction organization
Nectin/Necl trans heterodimerization
Adherens junctions interactions

Biological Process

homophilic cell adhesion via plasma membrane adhesion molecules
heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules
protein localization
adherens junction organization

Molecular Function

protein homodimerization activity

Cellular Component

plasma membrane
cell-cell junction
parallel fiber to Purkinje cell synapse
integral component of presynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368124
Coding exons: 10
Length: 31705
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125744
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.69	168	242	0.694	0.0000137	2789
Missense (PolyPhen)		42	81.713	0.514		928
Synonymous	0.0532	99	99.7	0.993	0.00000631	867
Loss of Function	3.74	3	21.9	0.137	0.00000115	241

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	0.000056	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the cell-cell adhesion. Has both calcium- independent homophilic cell-cell adhesion activity and calcium- independent heterophilic cell-cell adhesion activity with IGSF4, NECTIN1 and NECTIN3. Interaction with EPB41L1 may regulate structure or function of cell-cell junctions (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.459

Intolerance Scores

RVIS EVS: -0.49
RVIS percentile EVS: 22.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.468

Gene Damage Prediction

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