TMEM167A

Genetic evidence – Published PMID: 40924476 – Family 1 – one proband. Case-level (AR biallelic; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 PMID: 40924476 – Family 2 – one proband. Case-level (AR biallelic; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 PMID: 40924476 – Family 3 – one proband. Case-level (AR biallelic; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0; Case-control = 0 Family 3 total = 0.1 PMID: 40924476 – Family 4 – one proband. Case-level (AR compound heterozygous; non-LOF; each variant evaluated independently; no consanguinity deduction applied [not reported]) = 0.2; Segregation = 0; Case-control = 0 Family 4 total = 0.2 PMID: 40924476 – Family 5 – one proband. Case-level (AR predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [not reported]) = 1.5; Segregation = 0; Case-control = 0 Family 5 total = 1.5 PMID: 40924476 – Family 6 – one proband. Case-level (AR predicted null; loss-of-function mechanism plausible; no consanguinity deduction applied [not reported]) = 1.5; Segregation = 0; Case-control = 0 Family 6 total = 1.5 Published genetic evidence total = 4.4 / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (AR homozygous; non-LOF start = 0.1; consanguineous family) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 Family 2 – one proband. Case-level (AR homozygous; non-LOF start = 0.1; consanguineous family) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 Total genetic evidence (published AR + our cases) 4.4 (published AR) + 0.2 (our cases) = 4.6 / 12 Experimental evidence – Published PMID: 40924476 – Function / expression. Gene expression demonstrated in relevant tissues including pancreas and developing brain. Function/expression (supportive biological relevance) = 0.5 PMID: 40924476 – Functional alteration (non-patient β-cell line knockdown). Gene depletion increased susceptibility to ER-stress–induced apoptosis. Functional alteration (engineered cell model) = 0.5 PMID: 40924476 – Functional alteration (variant-specific iPSC-derived β cells). Variant impaired ER-to-Golgi trafficking and β-cell function in disease-relevant cells. Functional alteration (variant-specific, mechanistic support) = 1.0 PMID: 40924476 – Functional alteration (human β-cell transplantation assay). Mutant cells demonstrated reduced C-peptide secretion after transplantation into mice. Functional alteration (in vivo physiological assay; not full animal disease model) = 0.5 Experimental evidence total = 2.5 / 6 Overall score Genetic evidence = 4.6 Experimental evidence = 2.5 Overall score = 7.1 / 18

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM167A variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 7

Microcephaly, epilepsy, and diabetes syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_174909.5. 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						0
missense		1 clinvar	9 clinvar			10
nonsense						0
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	1	14	0	0	15

Highest pathogenic variant AF is 0.0000014022178

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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_174909.5	RefSeq	NP_777569.1	4	MANE Select
ENST00000502346.2	Ensembl	ENSP00000424707.1	4	MANE Select
ENST00000987056.1	Ensembl	ENSP00000656873.1	2	Standard
ENST00000987057.1	Ensembl	ENSP00000656874.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein secretion
intracellular transport

Cellular Component

Golgi membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000502346
Coding exons: 4
Length: 25018
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125718
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.411	32	39.2	0.815	0.00000192	463
Missense (PolyPhen)		3	5.7921	0.51794		84
Synonymous	0.140	12	12.6	0.950	5.40e-7	131
Loss of Function	0.0428	5	5.10	0.980	2.82e-7	57

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the early part of the secretory pathway. {ECO:0000269|PubMed:19942856}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

RVIS EVS: 0.06
RVIS percentile EVS: 58

Essentials

Essential (CRISPR): N
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.0000513

Gene Damage Prediction

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