MNS1

protein-coding

meiosis specific nuclear structural 1

Gene summary

This gene encodes a protein highly similar to the mouse meiosis-specific nuclear structural 1 protein. The mouse protein was shown to be expressed at the pachytene stage during spermatogenesis and may function as a nuclear skeletal protein to regulate nuclear morphology during meiosis. [provided by RefSeq, Oct 2008]

MANE transcript

NM_018365.4

Inheritance

ClinVar variants

P:12U:70B:6

Top phenotype

Heterotaxy, visceral, 9, autosomal, with male infertility

gnomAD constraint

pLI —, LoF o/e 0.99

Max pathogenic AF

—

Genomic locus

chr15:56,421,544-56,465,137

External References & Databases

Ensembl (ENSG00000138587)

Transcript & Mutation Effects

hg38 • Region Span ~43.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary ciliary dyskinesiaNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0016575

Submitter: ClinGen

The MNS1 gene was first reported in relation to spermiogenesis and motile ciliary function in 2012 (PMID:22396656). Primary Ciliary Dyskinesia (PCD) is a condition of impaired ciliary function characterized by neonates with respiratory distress, recurrent chest infections and cough (PMID: 31534215). Heterotaxy is present with approximately 50% penetrance, most often in the form of situs inversus totalis. Immotile sperm and female infertility are also reported for some affected patients. Given the overlap with MNS1 function as a microtubule inner protein (PMID:31668805) and PCD, this gene was evaluated for gene-disease association with PCD. At the time of this review at least one individual with a phenotype possibly consistent with PCD and a homozygous loss of function variant in MNS1 has been identified in the literature. However, other individuals in the family who were homozygous for this variant only presented with laterality defects or potential infertility (PMID:31534215). Other potential individuals with variants in MNS1 are present in the literature; however in these reports, conflicting or confounding data was also identified. For example, in one family, the proband presented with situs inversus totalis and features of PCD; however, this individual was also homozygous for a frameshift variant in another PCD gene. Other individuals in the family were also affected by PCD but did not carry the MNS1 variant. (PMID:30148830). Experimental evidence supporting this gene-disease relationship includes studies demonstrating that MNS1 localizes to tissue types relevant to disease and known to have motile cilia, evidence suggesting interaction between MNS1 and another known PCD gene (CCDC114), as well as a knockout mouse model that expresses laterality defects and sperm abnormalities (PMID:22396656, 30148830). Of note, there are other individuals who are published in the literature with variants in this gene, but with phenotypes that are not specific or detailed enough to support a relationship between MNS1 and PCD. In summary, MNS1 has a Disputed association to Primary Ciliary Dyskinesia based on a small number of experimental evidence data points. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 11th, 2022 (SOP Version 8).

heterotaxy, visceral, 9, autosomal, with male infertilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030070

Submitter: Labcorp Genetics (formerly Invitae)

heterotaxy, visceral, 9, autosomal, with male infertilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030070

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Heterotaxy, visceral, 9, autosomal, with male infertilityAR

Manifestation: Cardiovascular; Gastrointestinal; Genitourinary

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early identifcation and management

Refs: 30148830; 31534215

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MNS1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 62

Heterotaxy, visceral, 9, autosomal, with male infertilityTotal: 14

not providedTotal: 9

MNS1-related disorderTotal: 8

Primary ciliary dyskinesiaTotal: 4

Multiple congenital anomalies/dysmorphic syndrome-intellectual disabilityTotal: 2

Situs inversusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018365.4. 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				1 clinvar		1
missense			66 clinvar	5 clinvar		71
nonsense	1 clinvar	3 clinvar	3 clinvar			7
start loss						0
frameshift	4 clinvar	3 clinvar				7
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	5	7	70	6	0	88

Highest pathogenic variant AF is 0.0005019195

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018365.4	RefSeq	NP_060835.1	10	MANE Select
ENST00000260453.4	Ensembl	ENSP00000260453.3	10	MANE Select
ENST00000876520.1	Ensembl	ENSP00000546579.1	10	Standard
ENST00000876520.2	Ensembl	ENSP00000546579.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mns1	Danio rerio	Structure: otolith Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

mns1

Danio rerio

Structure: otolith

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

spermatogenesis
cilium organization
positive regulation of cilium assembly
meiotic cell cycle
left/right axis specification

Molecular Function

identical protein binding

Cellular Component

nuclear envelope
intermediate filament
axoneme
motile cilium
sperm flagellum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260453
Coding exons: 10
Length: 43594
Individuals with no LoFs: 125562
Homozygous LoFs: 0
Heterozygous LoFs: 174
Defined: 125736
p: 0.000692

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.439	270	250	1.08	0.0000130	3351
Missense (PolyPhen)		85	75.248	1.1296		1078
Synonymous	-0.554	84	77.8	1.08	0.00000363	742
Loss of Function	0.0721	32	32.4	0.986	0.00000171	394

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0.00043	0.00040	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00090	0.00087	rare
Finnish	0.000098	0.000092	rare
European (Non-Finnish)	0.00067	0.00066	rare
South Asian	0.0019	0.0018	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in the control of meiotic division and germ cell differentiation through regulation of pairing and recombination during meiosis. {ECO:0000250}.;

Recessive Scores

pRec: 0.115

Intolerance Scores

RVIS EVS: 0.13
RVIS percentile EVS: 63.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.642

Gene Damage Prediction

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