MFHAS1

Chr 8

multifunctional ROCO family signaling regulator 1

Also known as: LRRC65, MASL1, ROCO4

NCBI Gene: 9258 ENSG00000147324 UniProt: Q9Y4C4 OMIM: 605352

This protein is a GTP-binding protein that regulates Toll-like receptor signaling pathways in innate immunity and inflammatory responses, and also plays a role in erythrocyte differentiation through ERK1/ERK2 signaling. Mutations cause malignant fibrous histiocytoma, a type of soft tissue sarcoma. The inheritance pattern for this condition is not well-established in the provided information.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Identified in a human 8p amplicon, this gene is a potential oncogene whose expression is enhanced in some malignant fibrous histiocytomas (MFH). The primary structure of its product includes an ATP/GTP-binding site, three leucine zipper domains, and a leucine-rich tandem repeat, which are structural or functional elements for interactions among proteins related to the cell cycle, and which suggest that overexpression might be oncogenic with respect to MFH. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Malignant fibrous histiocytomaMIM #605352

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.82

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.36

OE 0.56 (0.39–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.94Z-score

OE missense 1.22 (1.15–1.29)

757 obs / 620.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.56 (0.39–0.82)

0≤0.351.4

Missense OE?1.22 (1.15–1.29)

0≤0.61.4

Synonymous OE?1.43

0≤1.21.6

LoF obs/exp: 19 / 33.8Missense obs/exp: 757 / 620.8Syn Z: -5.73

Background carrier burden — how many people carry a rare variant somewhere in MFHAS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

1,919 rare PASS variants

Rare truncating (LoF)

1 in 2,200

144 rare PASS variants

Rare synonymous (reference)

1 in 56

1,009 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MFHAS1. 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 43	1 in 2,400
South Asian	~43k	1 in 42	1 in 1,300
Remaining (unassigned)	~30k	1 in 38	1 in 840
European (Finnish)	~27k	1 in 120	≈ 1 in 6,300
Admixed American	~22k	1 in 36	1 in 2,700
African / African American	~21k	1 in 33	1 in 1,800
East Asian	~20k	1 in 39	≈ 1 in 4,800
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 3,100
Middle Eastern	~2,884	1 in 41	≈ 1 in 2,900

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 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓