Genetic Variant NM_002520.7:c.353-113_353-107delTTTTTTT (chr5-171392586-CTTTTTTT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002520.7(NPM1):c.353-113_353-107delTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 451,254 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

NPM1
NM_002520.7 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08

Publications

0 publications found

Variant links:

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: Orphanet, G2P
bone marrow failure syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NPM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPM1	NM_002520.7	MANE Select	c.353-113_353-107delTTTTTTT	intron	N/A	NP_002511.1	A0A0S2Z491
NPM1	NM_001355006.2		c.353-113_353-107delTTTTTTT	intron	N/A	NP_001341935.1	A0A0S2Z491
NPM1	NM_199185.4		c.353-113_353-107delTTTTTTT	intron	N/A	NP_954654.1	P06748-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPM1	ENST00000296930.10	TSL:1 MANE Select	c.353-123_353-117delTTTTTTT	intron	N/A	ENSP00000296930.5	P06748-1
NPM1	ENST00000517671.5	TSL:1	c.353-123_353-117delTTTTTTT	intron	N/A	ENSP00000428755.1	P06748-1
NPM1	ENST00000351986.10	TSL:1	c.353-123_353-117delTTTTTTT	intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes

AF:

0.00000701

AC:

AN:

142632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000324

AC:

AN:

308622

Hom.:

AF XY:

0.00000627

AC XY:

AN XY:

159420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

7546

American (AMR)

AF:

0.00

AC:

AN:

9200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9200

East Asian (EAS)

AF:

0.00

AC:

AN:

22418

South Asian (SAS)

AF:

0.00

AC:

AN:

14306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1338

European-Non Finnish (NFE)

AF:

0.00000486

AC:

AN:

205800

Other (OTH)

AF:

0.00

AC:

AN:

17830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000701

AC:

AN:

142632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69006

show subpopulations

African (AFR)

AF:

0.0000258

AC:

AN:

38830

American (AMR)

AF:

0.00

AC:

AN:

14312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

4940

South Asian (SAS)

AF:

0.00

AC:

AN:

4570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65274

Other (OTH)

AF:

0.00

AC:

AN:

1942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over