NM_002520.7:c.863_864insCCTG

Variant names:

• chr5-171410540-T-TCTGC
• rs1554138189
• NM_002520.7:c.863_864insCCTG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002520.7(NPM1):​c.863_864insCCTG​(p.Trp288CysfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPM1 NM_002520.7 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.24
• Publications: 0 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 congenita

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-171410540-T-TCTGC is Pathogenic according to our data. Variant chr5-171410540-T-TCTGC is described in ClinVar as Pathogenic. ClinVar VariationId is 14001.Status of the report is no_assertion_criteria_provided, 0 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.863_864insCCTG	p.Trp288CysfsTer12	frameshift	Exon 11 of 11	NP_002511.1
	NPM1	NM_001355006.2		c.863_864insCCTG	p.Trp288CysfsTer12	frameshift	Exon 12 of 12	NP_001341935.1
	NPM1	NM_199185.4		c.776_777insCCTG	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.863_864insCCTG	p.Trp288CysfsTer12	frameshift	Exon 11 of 11	ENSP00000296930.5
	NPM1	ENST00000517671.5	TSL:1	c.863_864insCCTG	p.Trp288CysfsTer12	frameshift	Exon 12 of 12	ENSP00000428755.1
	NPM1	ENST00000351986.10	TSL:1	c.776_777insCCTG	p.Trp259CysfsTer12	frameshift	Exon 10 of 10	ENSP00000341168.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1

Jan 20, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554138189; hg19: chr5-170837544; COSMIC: COSV51542815; COSMIC: COSV51542815;