THSD7A

Chr 7

thrombospondin type 1 domain containing 7A

NCBI Gene: 221981 ENSG00000005108 UniProt: Q9UPZ6 OMIM: 612249

The THSD7A protein inhibits endothelial cell migration and tube formation through interactions with integrin and paxillin, and plays a role in actin cytoskeleton rearrangement. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants (pLI=1.0, LOEUF=0.215), indicating that haploinsufficiency is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is found almost exclusively in endothelial cells from placenta and umbilical cord. The encoded protein appears to interact with alpha(V)beta(3) integrin and paxillin to inhibit endothelial cell migration and tube formation. This protein may be involved in cytoskeletal organization. Variations in this gene may be associated with low bone mineral density in osteoporosis. [provided by RefSeq, Aug 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.21

Clinical Summary— THSD7A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

274 VUS of 334 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 1.000

Z-score 8.06

OE 0.14 (0.09–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

-0.60Z-score

OE missense 1.06 (1.00–1.11)

947 obs / 896.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.14 (0.09–0.21)

0≤0.351.4

Missense OE?1.06 (1.00–1.11)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 14 / 101.7Missense obs/exp: 947 / 896.6Syn Z: -3.11

This gene — mechanism propensity

0.3693th %ile

GOF

0.4677th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.21

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

334 submitted variants in ClinVar

ClinVar

Classification Summary

VUS274

Likely Benign21

Benign9

Conflicting2

274

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	271	2	0	274
Likely Benign	0	9	5	7	21
Benign	0	2	1	6	9
Conflicting	—				2
Total	1	282	8	13	306

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

30 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap THSD7A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →