INSL6

Chr 9

insulin like 6

Also known as: RIF1

NCBI Gene: 11172 ENSG00000120210 UniProt: Q9Y581 OMIM: 606414

The protein encoded by INSL6 belongs to the insulin superfamily and may function in sperm development and fertilization, with expression restricted to testicular interstitial cells. Mutations in INSL6 cause autosomal recessive cryptorchidism with or without insulin-like factor 6 deficiency, affecting male reproductive development. The gene shows very low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene contains a classical signature of the insulin superfamily and is significantly similar to relaxin and relaxin-like factor. This gene is preferentially expressed in testis. Its expression in testis is restricted to interstitial cells surrounding seminiferous tubules, which suggests a role in sperm development and fertilization. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.92

Clinical Summary— INSL6

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.92LOEUF

pLI 0.000

Z-score -1.11

OE 1.43 (0.88–1.92)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.45Z-score

OE missense 1.62 (1.44–1.82)

201 obs / 124.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.43 (0.88–1.92)

0≤0.351.4

Missense OE?1.62 (1.44–1.82)

0≤0.61.4

Synonymous OE?1.59

0≤1.21.6

LoF obs/exp: 11 / 7.7Missense obs/exp: 201 / 124.1Syn Z: -3.20

This gene — mechanism propensity

0.79top 25%

GOF

0.2895th %ile

LOF

0.3453th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

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