TM2D3

Chr 15

TM2 domain containing 3

Also known as: BLP2, NCRMS

NCBI Gene: 80213 ENSG00000184277 UniProt: Q9BRN9

TM2D3 encodes a probable positive regulator of Notch signaling with structural similarity to G protein-coupled receptors. Biallelic mutations cause neurocardiorenal malformation syndrome, an autosomal recessive disorder affecting the nervous system, heart, and kidneys. The gene is highly constrained against loss-of-function variation (pLI near 0, LOEUF 1.69), indicating intolerance to functional disruption.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily. This protein has sequence and structural similarities to the beta-amyloid binding protein (BBP), but, unlike BBP, it does not regulate a response to beta-amyloid peptide. This protein may have regulatory roles in cell death or proliferation signal cascades. Several alternatively spliced transcript variants of this gene are described but the full length nature of some variants has not been determined. Multiple polyadenylation sites have been found in this gene. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNeurocardiorenal malformation syndrome

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.69

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.69LOEUF

pLI 0.000

Z-score -0.22

OE 1.07 (0.68–1.69)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.74Z-score

OE missense 1.17 (1.03–1.33)

174 obs / 148.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.07 (0.68–1.69)

0≤0.351.4

Missense OE?1.17 (1.03–1.33)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 12 / 11.2Missense obs/exp: 174 / 148.5Syn Z: -1.68

Background carrier burden — how many people carry a rare variant somewhere in TM2D3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 98

431 rare PASS variants

Rare truncating (LoF)

1 in 780

81 rare PASS variants

Rare synonymous (reference)

1 in 180

167 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TM2D3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 560
South Asian	~43k	1 in 180	1 in 920
Remaining (unassigned)	~30k	1 in 79	1 in 810
European (Finnish)	~27k	1 in 390	1 in 1,900
Admixed American	~22k	1 in 130	1 in 2,500
African / African American	~21k	1 in 100	1 in 600
East Asian	~20k	1 in 150	1 in 1,600
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓