PSMC3IP

protein-coding

PSMC3 interacting protein

Gene summary

This gene encodes a protein that functions in meiotic recombination. It is a subunit of the PSMC3IP/MND1 complex, which interacts with PSMC3/TBP1 to stimulate DMC1- and RAD51-mediated strand exchange during meiosis. The protein encoded by this gene can also co-activate ligand-driven transcription mediated by estrogen, androgen, glucocorticoid, progesterone, and thyroid nuclear receptors. Mutations in this gene cause XX female gonadal dysgenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2011]

MANE transcript

NM_016556.4

Inheritance

AR, AD

ClinVar variants

P:5U:38B:10

Top phenotype

Ovarian dysgenesis 3

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr17:42,572,310-42,577,831

External References & Databases

Ensembl (ENSG00000131470)

Transcript & Mutation Effects

hg38 • Region Span ~5.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ovarian dysgenesis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013689

Submitter: Labcorp Genetics (formerly Invitae)

ovarian dysgenesis 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013689

Submitter: Ambry Genetics

ovarian dysgenesis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013689

Submitter: PanelApp Australia

46 XX gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009299

Submitter: Orphanet

Clinical Genomic Database (CGD)

Ovarian dysgenesis 3AR

Manifestation: Endocrine; Genitourinary

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

Comments: To induce/maintain secondary sex characteristics, and to allow reproduction, specific interventions (eg, medical hormonal treatment) may be necessary

Refs: 21963259

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSMC3IP variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 35

not providedTotal: 26

PSMC3IP-related disorderTotal: 5

Ovarian dysgenesis 3Total: 5

46 XX gonadal dysgenesisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016556.4. 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				4 clinvar	3 clinvar	7
missense	1 clinvar	2 clinvar	36 clinvar	2 clinvar	1 clinvar	42
nonsense		1 clinvar				1
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	3	38	6	4	53

Highest pathogenic variant AF is 0.0005718336

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016556.4	RefSeq	NP_057640.1	8	MANE Select
ENST00000393795.8	Ensembl	ENSP00000377384.2	8	MANE Select
NM_001256014.2	RefSeq	NP_001242943.1	6	Standard
NM_001256015.2	RefSeq	NP_001242944.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Androgen receptor signaling pathway
AndrogenReceptor

Biological Process

DNA recombination
meiotic cell cycle
positive regulation of nucleic acid-templated transcription

Molecular Function

DNA binding
nuclear receptor transcription coactivator activity

Cellular Component

cellular_component
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393795
Coding exons: 8
Length: 5517
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.433	126	113	1.11	0.00000566	1436
Missense (PolyPhen)		40	36.118	1.1075		469
Synonymous	0.00191	44	44.0	1.00	0.00000238	373
Loss of Function	1.33	9	14.5	0.622	6.39e-7	181

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in meiotic recombination. Stimulates DMC1-mediated strand exchange required for pairing homologous chromosomes during meiosis. The complex PSMC3IP/MND1 binds DNA, stimulates the recombinase activity of DMC1 as well as DMC1 D-loop formation from double-strand DNA. This complex stabilizes presynaptic RAD51 and DMC1 filaments formed on single strand DNA to capture double-strand DNA. This complex stimulates both synaptic and presynaptic critical steps in RAD51 and DMC1- promoted homologous pairing. May inhibit HIV-1 viral protein TAT activity and modulate the activity of proteasomes through association with PSMC3. Acts as a tissue specific coactivator of hormone-dependent transcription mediated by nuclear receptors. {ECO:0000269|PubMed:10806355, ECO:0000269|PubMed:16407260, ECO:0000269|PubMed:21963259}.;
Disease: DISEASE: Ovarian dysgenesis 3 (ODG3) [MIM:614324]: A disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. {ECO:0000269|PubMed:21963259}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.908
RVIS EVS: -0.29
RVIS percentile EVS: 32.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.595

Gene Damage Prediction

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