CRIPT

protein-coding

CXXC repeat containing interactor of PDZ3 domain

Gene summary

This gene encodes a protein that binds to the PDZ3 peptide recognition domain. The encoded protein may modulates protein interactions with the cytoskeleton. A mutation in this gene resulted in short stature with microcephaly and distinctive facies. [provided by RefSeq, Jun 2014]

MANE transcript

NM_014171.6

Inheritance

ClinVar variants

P:13U:31B:12

Top phenotype

Rothmund-Thomson syndrome, type 3

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr2:46,616,416-46,685,037

External References & Databases

Ensembl (ENSG00000119878)

Transcript & Mutation Effects

hg38 • Region Span ~68.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Rothmund-Thomson syndrome type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014347

Submitter: Labcorp Genetics (formerly Invitae)

Rothmund-Thomson syndrome type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014347

Submitter: G2P

Rothmund-Thomson syndrome type 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014347

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Rothmund-Thomson syndrome, type 3AR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

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: 24389050; 27250922

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRIPT variants in ClinVar

8 Conditions Cataloged

not providedTotal: 59

Inborn genetic diseasesTotal: 20

Rothmund-Thomson syndrome type 3Total: 12

not specifiedTotal: 5

CRIPT-related disorderTotal: 4

Ateleiotic dwarfismTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014171.6. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				10 clinvar	1 clinvar	11
missense	1 clinvar	1 clinvar	31 clinvar	1 clinvar		34
nonsense	1 clinvar	1 clinvar				2
start loss	1 clinvar					1
frameshift	5 clinvar					5
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar				3
Total	9	4	31	11	1	56

Highest pathogenic variant AF is 0.0000664489

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014171.6	RefSeq	NP_054890.1	5	MANE Select
ENST00000238892.4	Ensembl	ENSP00000238892.3	5	MANE Select
ENST00000718244.1	Ensembl	ENSP00000520689.1	5	Standard
ENST00000718245.1	Ensembl	ENSP00000520690.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cytoplasmic microtubule organization
protein localization to microtubule
establishment of protein localization
regulation of postsynaptic density protein 95 clustering

Molecular Function

protein binding
microtubule binding
PDZ domain binding
protein-containing complex binding
scaffold protein binding

Cellular Component

fibrillar center
nucleus
nucleolus
cytoplasm
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000238892
Coding exons: 5
Length: 9327
Individuals with no LoFs: 125675
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125685
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.395	57	49.2	1.16	0.00000217	661
Missense (PolyPhen)		16	17.571	0.91058		235
Synonymous	0.398	14	16.0	0.873	7.58e-7	166
Loss of Function	0.519	5	6.42	0.779	2.69e-7	92

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)	0.000071	0.000070	rare
South Asian	0	0.0	absent
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the cytoskeletal anchoring of DLG4 in excitatory synapses. {ECO:0000250|UniProtKB:Q792Q4}.;
Disease: DISEASE: Short stature with microcephaly and distinctive facies (SSMF) [MIM:615789]: A disease characterized by dwarfism, microcephaly, and distinctive facial dysmorphism involving frontal bossing, high forehead, sparse hair and eyebrows, telecanthus, mild proptosis, anteverted nares, and flat nasal bridge. {ECO:0000269|PubMed:24389050, ECO:0000269|PubMed:27250922}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.688
RVIS EVS: -0.12
RVIS percentile EVS: 44.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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