chr5-171410542-T-TCCTG

Variant names:

• chr5-171410542-T-TCCTG
• rs1057519744
• NM_002520.7:c.862_863insCCTG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002520.7(NPM1):​c.862_863insCCTG​(p.Trp288SerfsTer12) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPM1 NM_002520.7 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09
• Publications: 2 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 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.
• PM2: Very rare variant in population databases, with high coverage

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.862_863insCCTG	p.Trp288SerfsTer12	frameshift	Exon 11 of 11	NP_002511.1
	NPM1	NM_001355006.2		c.862_863insCCTG	p.Trp288SerfsTer12	frameshift	Exon 12 of 12	NP_001341935.1
	NPM1	NM_199185.4		c.775_776insCCTG	p.Trp259SerfsTer12	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.862_863insCCTG	p.Trp288SerfsTer12	frameshift	Exon 11 of 11	ENSP00000296930.5
	NPM1	ENST00000517671.5	TSL:1	c.862_863insCCTG	p.Trp288SerfsTer12	frameshift	Exon 12 of 12	ENSP00000428755.1
	NPM1	ENST00000351986.10	TSL:1	c.775_776insCCTG	p.Trp259SerfsTer12	frameshift	Exon 10 of 10	ENSP00000341168.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

Splicing

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

Other links and lift over

dbSNP: rs1057519744; hg19: chr5-170837546;