SPDL1

protein-coding

spindle apparatus coiled-coil protein 1

Gene summary

This gene encodes a coiled-coil domain-containing protein that functions in mitotic spindle formation and chromosome segregation. The encoded protein plays a role in coordinating microtubule attachment by promoting recruitment of dynein proteins, and in mitotic checkpoint signaling. [provided by RefSeq, Jul 2016]

Previous symbols:

CCDC99

MANE transcript

NM_017785.5

Inheritance

ClinVar variants

U:92B:8

Top phenotype

Severe primary microcephaly

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr5:169,583,636-169,604,778

External References & Databases

Ensembl (ENSG00000040275)

Transcript & Mutation Effects

hg38 • Region Span ~21.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephalyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0001149

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPDL1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 90

not providedTotal: 6

Severe primary microcephalyTotal: 1

Neonatal deathTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017785.5. 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			1 clinvar	1 clinvar	1 clinvar	3
missense			90 clinvar	5 clinvar		95
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar	1 clinvar		2
Total	0	0	92	7	1	100

Highest pathogenic variant AF is 0.0000047919602

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017785.5	RefSeq	NP_060255.3	11	MANE Select
ENST00000265295.9	Ensembl	ENSP00000265295.4	11	MANE Select
NM_001329639.2	RefSeq	NP_001316568.1	10	Standard
NM_001329640.2	RefSeq	NP_001316569.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
Amplification of signal from the kinetochores
Mitotic Spindle Checkpoint
Cell Cycle Checkpoints

Biological Process

establishment of mitotic spindle orientation
mitotic metaphase plate congression
mitotic spindle assembly checkpoint
protein localization to kinetochore
cell division

Molecular Function

protein binding
enzyme binding
kinetochore binding

Cellular Component

spindle pole
condensed chromosome outer kinetochore
nucleus
microtubule organizing center
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265295
Coding exons: 11
Length: 21145
Individuals with no LoFs: 125495
Homozygous LoFs: 0
Heterozygous LoFs: 253
Defined: 125748
p: 0.00101

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.236	324	312	1.04	0.0000163	3989
Missense (PolyPhen)		95	103.98	0.91361		1434
Synonymous	-1.08	123	109	1.13	0.00000536	1063
Loss of Function	1.12	29	36.3	0.800	0.00000213	429

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00077	0.00069	rare
Ashkenazi Jewish	0.0049	0.0048	notable
East Asian	0.00047	0.00044	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.00066	0.00065	rare
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the localization of dynein and dynactin to the mitotic kintochore. Dynein is believed to control the initial lateral interaction between the kinetochore and spindle microtubules and to facilitate the subsequent formation of end-on kinetochore-microtubule attachments mediated by the NDC80 complex. Also required for correct spindle orientation. Does not appear to be required for the removal of spindle assembly checkpoint (SAC) proteins from the kinetochore upon bipolar spindle attachment (PubMed:17576797, PubMed:19468067). Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track) (PubMed:25035494). {ECO:0000255|HAMAP-Rule:MF_03041, ECO:0000269|PubMed:17576797, ECO:0000269|PubMed:19468067, ECO:0000269|PubMed:25035494}.;

Recessive Scores

pRec: 0.0826

Intolerance Scores

RVIS EVS: 1.25
RVIS percentile EVS: 93.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E

Gene Damage Prediction

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