SAMD9L

Chr 7AD

sterile alpha motif domain containing 9 like

ENSG00000177409 UniProt: Q8IVG5 OMIM: 611170

The protein functions as a tumor suppressor and mediates down-regulation of growth factor signaling via internalization of growth factor receptors, while also playing a role in endosome fusion and the innate immune response to viral infection. Mutations cause ataxia-pancytopenia syndrome and spinocerebellar ataxia 49, as well as myeloid disorders including juvenile myelomonocytic leukemia and myelodysplastic syndrome. The gene follows autosomal dominant inheritance and is highly intolerant to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

May be involved in endosome fusion. Mediates down-regulation of growth factor signaling via internalization of growth factor receptors

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.783 OMIM phenotypes

Clinical Summary— SAMD9L

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Gene-Disease Validity (ClinGen)

SAMD9L-related spectrum and myeloid neoplasm risk · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.000

Z-score 2.86

OE 0.58 (0.44–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.63Z-score

OE missense 0.84 (0.78–0.89)

661 obs / 790.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.44–0.78)

0≤0.351.4

Missense OE?0.84 (0.78–0.89)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 32 / 54.9Missense obs/exp: 661 / 790.3Syn Z: -0.51

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSAMD9L-related ataxia-pancytopenia syndromeOTHERAD

This gene — mechanism propensity

0.6840th %ile

GOF

0.6151th %ile

LOF

0.2289th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOF1 literature citation

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFAtaxia pancytopenia (ATXPC) syndrome due to gain-of-function pathogenic variants in the SAMD9L gene has been described in 38 patients to date.1

LOFThese findings suggest that haploinsufficiency of SAMD9L and/or SAMD9 gene(s) contributes to myeloid transformation.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References