LRWD1

protein-coding

leucine rich repeats and WD repeat domain containing 1, the group of MicroRNA protein coding host genes|WD repeat domain containing

Gene summary

The protein encoded by this gene interacts with components of the origin recognition complex (ORC) and regulates the formation of the prereplicative complex. The encoded protein stabilizes the ORC and therefore aids in DNA replication. This protein is required for the G1/S phase transition of the cell cycle. In addition, the encoded protein binds to trimethylated histone H3 in heterochromatin and recruits the ORC and lysine methyltransferases, which help maintain the repressive heterochromatic state. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

MANE transcript

NM_152892.3

Inheritance

—

ClinVar variants

U:127B:8

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr7:102,464,956-102,473,168

External References & Databases

Ensembl (ENSG00000161036)

Transcript & Mutation Effects

hg38 • Region Span ~8.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LRWD1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 124

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152892.3. 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	1 clinvar		3
missense			123 clinvar	6 clinvar	1 clinvar	130
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	127	7	1	135

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152892.3	RefSeq	NP_690852.1	15	MANE Select
ENST00000292616.10	Ensembl	ENSP00000292616.5	15	MANE Select
NM_001317721.2	RefSeq	NP_001304650.1	12	Standard
ENST00000463739.5	Ensembl	ENSP00000420650.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

DNA replication initiation
chromatin organization
establishment of protein localization to chromatin

Molecular Function

chromatin binding
protein binding
methyl-CpG binding
methylated histone binding

Cellular Component

kinetochore
condensed chromosome kinetochore
nucleus
nuclear origin of replication recognition complex
pericentric heterochromatin

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292616
Coding exons: 15
Length: 8240
Individuals with no LoFs: 125651
Homozygous LoFs: 0
Heterozygous LoFs: 95
Defined: 125746
p: 0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.229	408	395	1.03	0.0000252	4089
Missense (PolyPhen)		157	161.2	0.97396		1675
Synonymous	-3.30	239	182	1.31	0.0000131	1321
Loss of Function	0.164	31	32.0	0.969	0.00000146	345

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00028	0.00027	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00051	0.00047	rare
South Asian	0.00029	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for G1/S transition. Recruits and stabilizes the origin recognition complex (ORC) onto chromatin during G1 to establish pre-replication complex (preRC) and to heterochromatic sites in post-replicated cells. Binds a combination of DNA and histone methylation repressive marks on heterochromatin. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3 in a cooperative manner with DNA methylation. Required for silencing of major satellite repeats. May be important ORC2, ORC3 and ORC4 stability. {ECO:0000269|PubMed:20850016, ECO:0000269|PubMed:20932478, ECO:0000269|PubMed:21029866, ECO:0000269|PubMed:22427655, ECO:0000269|PubMed:22645314}.;

Intolerance Scores

LoFtool: 0.815
RVIS EVS: 0.03
RVIS percentile EVS: 55.83

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.492

Gene Damage Prediction

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