RSPRY1

Chr 16AR

ring finger and SPRY domain containing 1

Also known as: SEMDFA

NCBI Gene: 89970 ENSG00000159579 UniProt: Q96DX4 OMIM: 616585

RSPRY1 encodes a glycoprotein containing a RING-type zinc finger domain and an SPRY domain. Biallelic mutations cause spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, an autosomal recessive skeletal dysplasia affecting the spine and long bones. This gene is highly constrained against loss-of-function variants in the population.

OMIM ResearchSummary from RefSeq, OMIM

This gene encodes a glycoprotein that contains a RING-type zinc finger domain and an SPRY domain of unknown function. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spondyloepimetaphyseal dysplasia, Faden-Alkuraya typeMIM #616723

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.03

OE 0.06 (0.02–0.19)

Highly constrained

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

Missense Constraint?

3.36Z-score

OE missense 0.47 (0.41–0.54)

150 obs / 318.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.19)

0≤0.351.4

Missense OE?0.47 (0.41–0.54)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 2 / 33.3Missense obs/exp: 150 / 318.9Syn Z: 1.26

Background carrier burden — how many people carry a rare variant somewhere in RSPRY1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

517 rare PASS variants

Rare truncating (LoF)

1 in 2,600

52 rare PASS variants

Rare synonymous (reference)

1 in 140

256 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RSPRY1. 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 300	1 in 2,900
South Asian	~43k	1 in 150	1 in 4,200
Remaining (unassigned)	~30k	1 in 170	≈ 1 in 7,500
European (Finnish)	~27k	1 in 780	≈ 1 in 27,000
Admixed American	~22k	1 in 130	1 in 1,500
African / African American	~21k	1 in 190	1 in 3,800
East Asian	~20k	1 in 130	1 in 710
Ashkenazi Jewish	~13k	1 in 310	none seen
Middle Eastern	~2,884	1 in 360	≈ 1 in 1,400

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): 9 of 14 coding exons well covered in gnomAD exomes; exons 3, 4, 6, 12, 15 marginal. Genomes: all 14.? see exons ↓