TMEM45A

Genetic evidence – Published PMID: 34410316 – Family 1 – two affected sibs (counted as one proband). Case-level (AR biallelic predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [non-consanguineous]) = 1.5; Segregation (two affected sibs segregating with biallelic variants; parents confirmed heterozygous carriers) = 0.5; Case-control = 0 Family 1 total = 2.0 PMID: 34410316 – Family 2 – one proband. Case-level (AR biallelic predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [non-consanguineous]) = 1.5; Segregation = 0; Case-control = 0 Family 2 total = 1.5 PMID: 34410316 – Family 3 – one proband. Case-level (AR compound heterozygous predicted null; loss-of-function mechanism plausible; each variant evaluated independently; no consanguinity deduction applied [non-consanguineous]) = 3; Segregation = 0; Case-control = 0 Family 3 total = 3 Published genetic evidence total = 6.5 / 12 Genetic evidence – Our case Family 1 – one proband. Case-level (AR homozygous predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [consanguinity not documented]) = 1.5; Segregation = 0; Case-control = 0 Family 1 total = 1.5 Total genetic evidence (published AR + our case) 5.0 (published AR) + 1.5 (our case) = 8 / 12 Experimental evidence – Published PMID: 34410316 – Function / expression. TMEM45A expression demonstrated in human corneal tissue, supporting biological relevance to ocular phenotype. Function/expression = 0.5 PMID: 34410316 – Model system (knockout mouse). Knockout mice demonstrated corneal stromal thinning and structural abnormalities consistent with keratoglobus-like pathology. Model system (conservative scoring) = 1.0 Experimental evidence total = 1.5 / 6 Overall score Genetic evidence = 8 Experimental evidence = 1.5 Overall score = 9.5 / 18

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM45A variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 40

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018004.3. 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			2
missense			36 clinvar	4 clinvar		40
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	41	4	0	45

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018004.3	RefSeq	NP_060474.1	5	MANE Select
ENST00000323523.8	Ensembl	ENSP00000319009.4	5	MANE Select
NM_001363876.2	RefSeq	NP_001350805.1	6	Standard
ENST00000403410.5	Ensembl	ENSP00000385089.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000323523
Coding exons: 5
Length: 84826
Individuals with no LoFs: 125686
Homozygous LoFs: 0
Heterozygous LoFs: 62
Defined: 125748
p: 0.000247

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.632	124	145	0.853	0.00000712	1791
Missense (PolyPhen)		24	36.547	0.65669		485
Synonymous	0.211	50	51.9	0.963	0.00000247	526
Loss of Function	1.94	6	13.8	0.435	7.37e-7	158

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.0043	0.0043	notable
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000098	0.000098	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.0902

Intolerance Scores

LoFtool: 0.646
RVIS EVS: -0.16
RVIS percentile EVS: 41.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.754

Gene Damage Prediction

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