rs587776806
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPP5_Moderate
The NM_002520.7(NPM1):c.860_863dupTCTG(p.Trp288CysfsTer12) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NPM1
NM_002520.7 frameshift
NM_002520.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.84
Publications
143 publications found
Genes affected
NPM1 (HGNC:7910): (nucleophosmin 1) The protein encoded by this gene is involved in several cellular processes, including centrosome duplication, protein chaperoning, and cell proliferation. The encoded phosphoprotein shuttles between the nucleolus, nucleus, and cytoplasm, chaperoning ribosomal proteins and core histones from the nucleus to the cytoplasm. This protein is also known to sequester the tumor suppressor ARF in the nucleolus, protecting it from degradation until it is needed. Mutations in this gene are associated with acute myeloid leukemia. Dozens of pseudogenes of this gene have been identified. [provided by RefSeq, Aug 2017]
NPM1 Gene-Disease associations (from GenCC):
- dyskeratosis congenitaInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PP5
Variant 5-171410539-C-CTCTG is Pathogenic according to our data. Variant chr5-171410539-C-CTCTG is described in ClinVar as Pathogenic. ClinVar VariationId is 13998.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002520.7. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NPM1 | NM_002520.7 | MANE Select | c.860_863dupTCTG | p.Trp288CysfsTer12 | frameshift | Exon 11 of 11 | NP_002511.1 | ||
| NPM1 | NM_001355006.2 | c.860_863dupTCTG | p.Trp288CysfsTer12 | frameshift | Exon 12 of 12 | NP_001341935.1 | |||
| NPM1 | NM_199185.4 | c.773_776dupTCTG | p.Trp259CysfsTer12 | frameshift | Exon 10 of 10 | NP_954654.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NPM1 | ENST00000296930.10 | TSL:1 MANE Select | c.860_863dupTCTG | p.Trp288CysfsTer12 | frameshift | Exon 11 of 11 | ENSP00000296930.5 | ||
| NPM1 | ENST00000517671.5 | TSL:1 | c.860_863dupTCTG | p.Trp288CysfsTer12 | frameshift | Exon 12 of 12 | ENSP00000428755.1 | ||
| NPM1 | ENST00000351986.10 | TSL:1 | c.773_776dupTCTG | p.Trp259CysfsTer12 | frameshift | Exon 10 of 10 | ENSP00000341168.6 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 150500Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
0
AN:
150500
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.14e-7 AC: 1AN: 1400864Hom.: 0 Cov.: 26 AF XY: 0.00000143 AC XY: 1AN XY: 697832 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1400864
Hom.:
Cov.:
26
AF XY:
AC XY:
1
AN XY:
697832
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
31074
American (AMR)
AF:
AC:
0
AN:
39106
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25208
East Asian (EAS)
AF:
AC:
0
AN:
38874
South Asian (SAS)
AF:
AC:
0
AN:
78896
European-Finnish (FIN)
AF:
AC:
0
AN:
40390
Middle Eastern (MID)
AF:
AC:
0
AN:
4148
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1084874
Other (OTH)
AF:
AC:
1
AN:
58294
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome 0.00 AC: 0AN: 150500Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 73268
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
150500
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
73268
African (AFR)
AF:
AC:
0
AN:
40878
American (AMR)
AF:
AC:
0
AN:
15130
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3458
East Asian (EAS)
AF:
AC:
0
AN:
5150
South Asian (SAS)
AF:
AC:
0
AN:
4788
European-Finnish (FIN)
AF:
AC:
0
AN:
9996
Middle Eastern (MID)
AF:
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67806
Other (OTH)
AF:
AC:
0
AN:
2070
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
2
-
-
Acute myeloid leukemia (2)
1
-
-
Myelodysplastic syndrome progressed to acute myeloid leukemia (1)
1
-
-
NPM1-related disorder (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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