# NM_030943.4(AMN):c.948del (p.Glu317fs)

https://sugi.bio/variant/amn-p-glu317fs

## Summary

**AMN p.Glu317fs (c.948del)** is classified **Uncertain significance** in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). No gnomAD frequency available for this variant; Associated with Imerslund-Grasbeck syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2139312056 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AMN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Imerslund-Grasbeck syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Finland) |
| Diagnostic panels | AMN is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Imerslund-Gräsbeck syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased circulating vitamin B12 concentration — Obligate (100%)
- Malabsorption of Vitamin B12 — Obligate (100%)
- Abnormal blood 5-methyltetrahydrofolate level — Obligate (100%)
- Megaloblastic anemia — Very frequent (99-80%)
- Macrocytic anemia — Very frequent (99-80%)
- Hypersegmentation of neutrophil nuclei — Very frequent (99-80%)
- Proteinuria — Frequent (79-30%)
- Pallor — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007006/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AMN](https://sugi.bio/atlas/gene/AMN/) |
| Protein change (HGVS p.) | p.Glu317fs |
| Coding change (HGVS c.) | c.948del |
| MANE Select transcript | [NM_030943](https://www.ncbi.nlm.nih.gov/nuccore/NM_030943) |
| dbSNP | [rs2139312056](https://www.ncbi.nlm.nih.gov/snp/rs2139312056/) |
| Variant type | Deletion |
| Location | chr14:102930026-102930026 (GRCh38) |
| ClinVar | [VCV1378412](https://www.ncbi.nlm.nih.gov/clinvar/variation/1378412/) |

**All HGVS expressions:** `LRG_642:g.12373del`, `NC_000014.8:g.103396365del`, `NC_000014.9:g.102930028del`, `NG_008276.2:g.12373del`, `NM_030943.4:c.948del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.666, GERP -1.38, phastCons 0.101 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.446, pLI 1.8277e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AMN** population constraint: LOEUF 1.446, pLI 1.8277e-15, missense-Z -2.732; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.78, 61% of residues very-high.

**1 experimental structure(s)** (PDB): [6GJE](https://www.rcsb.org/structure/6GJE).

## What this gene does {#gene-function}

*Describes the biological roles of AMN (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AMN's established molecular role includes signaling receptor binding. In Reactome, AMN is annotated in disease pathway(s) including **Defective AMN causes MGA1**, **Defective CUBN causes MGA1**.

**Disease mechanism (Reactome):** AMN loss or alteration is curated in [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462), [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463).

### Pathways affected {#pathways}

AMN participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462) | other |
| ⚕ [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463) | other |
| [HDL clearance](https://reactome.org/content/detail/R-HSA-8964011) | other |
| [Uptake of dietary cobalamins into enterocytes](https://reactome.org/content/detail/R-HSA-9758881) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** signaling receptor binding, cargo receptor activity.

**Biological process:** receptor-mediated endocytosis, cobalamin metabolic process, cobalamin transport, Golgi to plasma membrane protein transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-04 |

## Associated conditions {#conditions}

[Imerslund-Grasbeck syndrome](https://sugi.bio/atlas/disease/imerslund-grasbeck-syndrome/).

**Reported phenotype names (ClinVar):** Imerslund-Grasbeck syndrome, Imerslund-Gräsbeck syndrome, ENTEROCYTE COBALAMIN MALABSORPTION, ENTEROCYTE INTRINSIC FACTOR RECEPTOR, DEFECT OF, PERNICIOUS ANEMIA, JUVENILE, DUE TO SELECTIVE INTESTINAL MALABSORPTION OF VITAMIN B12, WITH PROTEINURIA, Megaloblastic anemia due to inborn errors of metabolism.

## Similar variants {#similar}

Related AMN variant pages (same residue, condition, or type): [AMN c.138_162+20del](/variant/amn-c-138-162-plus-20del), [AMN c.208-13_211del](/variant/amn-c-208-minus-13-211del), [AMN c.844-14_845del](/variant/amn-c-844-minus-14-845del), [AMN p.Gly5fs](/variant/amn-p-gly5fs), [AMN c.513+2del](/variant/amn-c-513-plus-2del), [AMN p.Arg323fs](/variant/amn-p-arg323fs), [AMN p.Asn27fs](/variant/amn-p-asn27fs), [AMN p.Gln12fs](/variant/amn-p-gln12fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1378412). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*