chr5-171410541-C-CTGCA

Position:

• chr5-171410541-C-CTGCA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_002520.7(NPM1):​c.863_864insCATG​(p.Trp288CysfsTer12) variant causes a frameshift change. 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: 4.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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. Fraction of 0.0271 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-171410541-C-CTGCA is Pathogenic according to our data. Variant chr5-171410541-C-CTGCA is described in ClinVar as [Pathogenic]. Clinvar id is 13999.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPM1	NM_002520.7	c.863_864insCATG	p.Trp288CysfsTer12	frameshift_variant	11/11	ENST00000296930.10	NP_002511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPM1	ENST00000296930.10	c.863_864insCATG	p.Trp288CysfsTer12	frameshift_variant	11/11	1	NM_002520.7	ENSP00000296930	P1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 20, 2005

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554138188; hg19: chr5-170837545;