MS4A4A

Chr 11

membrane spanning 4-domains A4A

Also known as: 4SPAN1, CD20-L1, CD20L1, HDCME31P, MS4A4, MS4A7

NCBI Gene: 51338 ENSG00000110079 UniProt: Q96JQ5

MS4A4A encodes a membrane-spanning protein that may function in signal transduction as part of a multimeric receptor complex, with expression in hematopoietic cells and other tissues. The gene is not highly constrained against loss-of-function variants (pLI = 0.000008, LOEUF = 1.35), and no established Mendelian diseases have been definitively linked to MS4A4A mutations in pediatric populations. This gene is primarily studied in the context of immune system function rather than pediatric neurological disorders.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features, similar intron/exon splice boundaries, and display unique expression patterns in hematopoietic cells and nonlymphoid tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.35

LOEUF

Multiple*

Mechanism· predicted

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?

1.35LOEUF

pLI 0.000

Z-score 0.70

OE 0.78 (0.47–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.25Z-score

OE missense 0.94 (0.81–1.09)

118 obs / 125.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.78 (0.47–1.35)

0≤0.351.4

Missense OE?0.94 (0.81–1.09)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 9 / 11.6Missense obs/exp: 118 / 125.9Syn Z: 0.30

Background carrier burden — how many people carry a rare variant somewhere in MS4A4A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

352 rare PASS variants

Rare truncating (LoF)

1 in 330

79 rare PASS variants

Rare synonymous (reference)

1 in 220

104 rare PASS variants

Rare missense and truncating variants are carried at similar rates in MS4A4A; this gene does not show strong loss-of-function constraint by this measure. 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 150	1 in 370
South Asian	~43k	1 in 160	1 in 450
Remaining (unassigned)	~30k	1 in 170	1 in 160
European (Finnish)	~27k	1 in 1,300	1 in 2,200
Admixed American	~22k	1 in 110	1 in 370
African / African American	~21k	1 in 170	1 in 210
East Asian	~20k	1 in 110	1 in 360
Ashkenazi Jewish	~13k	1 in 1,400	1 in 1,700
Middle Eastern	~2,884	1 in 160	≈ 1 in 950

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): 6 of 7 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 7.? see exons ↓