SUN1

protein-coding

Sad1 and UNC84 domain containing 1, the group of SUN family

Gene summary

This gene is a member of the unc-84 homolog family and encodes a nuclear envelope protein with an Unc84 (SUN) domain. The protein is involved in nuclear anchorage and migration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2019]

Previous symbols:

UNC84A

MANE transcript

NM_001130965.3

Inheritance

ClinVar variants

U:345B:194

Top phenotype

Emery-Dreifuss muscular dystrophy

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr7:816,615-896,435

External References & Databases

Ensembl (ENSG00000164828)

Transcript & Mutation Effects

hg38 • Region Span ~79.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published PMID: 31170314 – Family 1 – one proband. Case-level (AR compound heterozygous; one predicted null splice variant + one non-LOF missense; each variant evaluated independently; no consanguinity deduction applied) = 1.6; Segregation = 0; Case-control = 0 Family 1 total = 1.6 Published genetic evidence total = 1.6 / 12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous frameshift; no consanguinity deduction applied) = 1.5; Segregation = 0; Case-control = 0 Family 1 total = 1.5 Family 2 – One proband. Case-level (biallelic predicted null in AR model; homozygous nonsense; no consanguinity deduction applied) = 1.5; Segregation = 0;Case-control = 0 Family 2 total = 1.5 Total genetic evidence (published AR + our cases) 1.6 (published AR) + 3.0 (our cases) = 3.6 / 12 Experimental evidence – Published PMID: 19874786 – SUN1/2 knockout mouse models demonstrate disrupted neuronal migration and cortical layering defects, supporting a role for SUN1 in neurogenesis and nuclear positioning during brain development. Model system (animal model supporting gene function in neurodevelopment; not mutation-specific) = 1.0 Gene function / biological plausibility (SUN1 participates in LINC complex linking nucleus to cytoskeleton during neuronal migration) = 1.0 Experimental evidence total = 1.5 / 6 Overall score Genetic evidence = 3.6 Experimental evidence = 2.0 Overall score = 5.6 / 18

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SUN1 variants in ClinVar

4 Conditions Cataloged

Emery-Dreifuss muscular dystrophyTotal: 597

not specifiedTotal: 153

not providedTotal: 46

SUN1-related disorderTotal: 31

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001130965.3. 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			5 clinvar	147 clinvar	6 clinvar	158
missense			316 clinvar	31 clinvar	10 clinvar	357
nonsense			6 clinvar			6
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			13 clinvar			13
Total	0	0	345	178	16	539

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 449 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001130965.3	RefSeq	NP_001124437.1	19	MANE Select
ENST00000401592.6	Ensembl	ENSP00000384015.1	19	MANE Select
NM_001171944.2	RefSeq	NP_001165415.1	16	Standard
NM_001171945.2	RefSeq	NP_001165416.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ossification
nuclear envelope organization
synapsis
spermatogenesis
response to mechanical stimulus

Molecular Function

protein binding
lamin binding
protein membrane anchor

Cellular Component

nuclear envelope
integral component of nuclear inner membrane
cytoplasm
nuclear membrane
meiotic nuclear membrane microtubule tethering complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000401592
Coding exons: 19
Length: 80545
Individuals with no LoFs: 124766
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 124814
p: 0.000192

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.331	474	495	0.958	0.0000322	5066
Missense (PolyPhen)		127	177.48	0.71557		1881
Synonymous	-1.19	246	223	1.10	0.0000171	1569
Loss of Function	3.92	17	45.5	0.374	0.00000240	461

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00046	0.00039	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00028	0.00028	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00024	0.00023	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton (PubMed:18039933, PubMed:18396275). The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning (By similarity). Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration (By similarity). Involved in telomere attachment to nuclear envelope in the prophase of meiosis implicating a SUN1/2:KASH5 LINC complex in which SUN1 and SUN2 seem to act at least partial redundantly (By similarity). Required for gametogenesis and involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis (By similarity). Helps to define the distribution of nuclear pore complexes (NPCs) (By similarity). Required for efficient localization of SYNE4 in the nuclear envelope (By similarity). May be involved in nuclear remodeling during sperm head formation in spermatogenenis (By similarity). May play a role in DNA repair by suppressing non- homologous end joining repair to facilitate the repair of DNA cross-links (PubMed:24375709). {ECO:0000250|UniProtKB:Q9D666, ECO:0000269|PubMed:18039933, ECO:0000269|PubMed:18396275, ECO:0000269|PubMed:24375709}.;

Recessive Scores

pRec: 0.0877

Intolerance Scores

LoFtool: 0.725
RVIS EVS: 0.83
RVIS percentile EVS: 88.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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