TMEM98

protein-coding

transmembrane protein 98

Gene summary

This gene encodes a transmembrane protein. A missense mutation in this gene result in Nanophthalmos 4 (NNO4). Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2014]

MANE transcript

NM_015544.3

Inheritance

ClinVar variants

P:3U:39B:6

Top phenotype

Nanophthalmos 4

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr17:32,927,910-32,945,106

External References & Databases

Ensembl (ENSG00000006042)

Transcript & Mutation Effects

hg38 • Region Span ~17.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nanophthalmos 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014426

Submitter: Ambry Genetics

nanophthalmos 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014426

Submitter: G2P

nanophthalmos 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014426

Submitter: PanelApp Australia

nanophthalmos 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014426

Submitter: Labcorp Genetics (formerly Invitae)

nanophthalmos 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014426

Submitter: ClinGen

*TMEM98* was first reported in relation to autosomal dominant nanophthalmos in 2014 (Awadalla et al., PMID:24852644). Affected individuals present with a short axial length, hyperopia and often angle-closure glaucoma. At least four unique variants, three missense and one deletion, have been reported in humans. Evidence supporting this gene-disease relationship includes. case-level data, segregation data, and experimental data. This gene-disease relationship is supported by experimental evidence that demonstrates the expression of this gene in relevant tissues (PMID:24852644). Variants in this gene have been reported in at least 5 probands in 4 publications (PMIDs:24852644, 26392740, 33203948, 33596443). Variants in this gene segregated with disease in 43 additional family members. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology GCEP on the meeting date April 17, 2025 (SOP Version 11).

nanophthalmiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005514

Submitter: Orphanet

Clinical Genomic Database (CGD)

Nanophthalmos 4AD

Manifestation: Ophthalmologic

Intervention: Ophthalmologic

Rationale: As the condition can include glaucoma, surveillance can allow early interventions that may potentially be beneficial related to preservation of visual status

Refs: 24852644

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM98 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 33

Nanophthalmos 4Total: 3

TMEM98-related disorderTotal: 3

not providedTotal: 2

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015544.3. 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			1 clinvar	3 clinvar	1 clinvar	5
missense	2 clinvar		33 clinvar		1 clinvar	36
nonsense				1 clinvar		1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar		5 clinvar			6
Total	3	0	39	4	2	48

Highest pathogenic variant AF is 6.8404785e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015544.3	RefSeq	NP_056359.2	6	MANE Select
ENST00000579849.6	Ensembl	ENSP00000463245.1	6	MANE Select
NM_001033504.2	RefSeq	NP_001028676.1	6	Standard
NM_001301746.2	RefSeq	NP_001288675.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

endoplasmic reticulum
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000579849
Coding exons: 6
Length: 17197
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125747
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.728	110	134	0.823	0.00000755	1441
Missense (PolyPhen)		5	10.355	0.48285		114
Synonymous	0.152	53	54.4	0.974	0.00000325	474
Loss of Function	1.85	5	11.9	0.421	7.54e-7	116

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Intolerance Scores

LoFtool: 0.493
RVIS EVS: 0.04
RVIS percentile EVS: 56.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.406

Gene Damage Prediction

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