Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_002520.7 | MANE Select | 1320 nt | 101–985 |
| NM_002520.5 | Alternative | 1373 nt | 156–1040 |
| NM_002520.6 | RefSeq Select | 1449 nt | 246–1130 |
| NM_002520.4 | Alternative | 1350 nt | 97–981 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -26 bp |
| Donor Loss (DL) | 0.0 | -271 bp |
| Acceptor Gain (AG) | 0.0 | 102 bp |
| Donor Gain (DG) | 0.0 | 221 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a synonymous variant (c.873G>A, p.R291=), which does not create a null allele. Therefore, this criterion is not applied at Not Applied strength because a synonymous change does not meet the definition of a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no previously established pathogenic variant at amino acid R291 has been reported. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant causing the same amino acid change.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no pedigree or de novo data are available. Therefore, this criterion is not applied at Not Applied strength due to lack of de novo confirmation.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been assessed.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or case series data. Therefore, this criterion is not applied at Not Applied strength due to absence of population‐based enrichment data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: R291 is not within a known mutational hotspot or critical domain of NPM1. Therefore, this criterion is not applied at Not Applied strength because the variant does not reside in a defined hotspot or domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: MAF = 0.0128% overall (0.11% in South Asians) with no homozygotes in gnomAD. Therefore, this criterion is applied at Moderate strength because the variant is present at an extremely low frequency consistent with rarity.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant" (for recessive disorders). The evidence for this variant shows: no data on trans occurrence with a pathogenic allele. Therefore, this criterion is not applied at Not Applied strength due to lack of trans observation.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a synonymous change without any indel or protein length alteration. Therefore, this criterion is not applied at Not Applied strength because there is no change in protein length.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: this is a synonymous change, not missense. Therefore, this criterion is not applied at Not Applied strength.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo assumption is documented. Therefore, this criterion is not applied at Not Applied strength.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied at Not Applied strength due to absence of segregation information.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: CADD score 1.03 and SpliceAI 0, predicting no deleterious impact. Therefore, this criterion is not applied at Not Applied strength because computational data do not support a deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or clinical context provided. Therefore, this criterion is not applied at Not Applied strength.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not found in ClinVar or other reputable sources as pathogenic. Therefore, this criterion is not applied at Not Applied strength.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF 0.0128%, which is far below a BA1 threshold (>5%). Therefore, this criterion is not applied at Not Applied strength.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: MAF remains below thresholds for BS1. Therefore, this criterion is not applied at Not Applied strength.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows: no healthy adult observation data. Therefore, this criterion is not applied at Not Applied strength.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied at Not Applied strength.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no phasing data. Therefore, this criterion is not applied at Not Applied strength.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a single nucleotide change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: CADD score 1.03 and SpliceAI scores of 0, predicting no effect. Therefore, this criterion is applied at Supporting strength because computational analyses consistently predict no functional impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case report with an alternate molecular basis. Therefore, this criterion is not applied at Not Applied strength.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no such report exists. Therefore, this criterion is not applied at Not Applied strength.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: c.873G>A is synonymous and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because it is a silent change without splicing effects.