Genetic Variant NPM1:c.353-111_353-107delTTTTT (chr5-171392586-CTTTTT-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002520.7(NPM1):c.353-111_353-107delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 450,326 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00073 ( 1 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 30 AD gene.

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.353-111_353-107delTTTTT	intron	N/A	NP_002511.1	A0A0S2Z491
NPM1	NM_001355006.2		c.353-111_353-107delTTTTT	intron	N/A	NP_001341935.1	A0A0S2Z491
NPM1	NM_199185.4		c.353-111_353-107delTTTTT	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_353-119delTTTTT	intron	N/A	ENSP00000296930.5	P06748-1
NPM1	ENST00000517671.5	TSL:1	c.353-123_353-119delTTTTT	intron	N/A	ENSP00000428755.1	P06748-1
NPM1	ENST00000351986.10	TSL:1	c.353-123_353-119delTTTTT	intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

142628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000140

Gnomad ASJ

AF:

0.000296

Gnomad EAS

AF:

0.000202

Gnomad SAS

AF:

0.000219

Gnomad FIN

AF:

0.000244

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000169

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000728

AC:

224

AN:

307652

Hom.:

AF XY:

0.000730

AC XY:

116

AN XY:

158900

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000398

AC:

AN:

7536

American (AMR)

AF:

0.000872

AC:

AN:

9170

Ashkenazi Jewish (ASJ)

AF:

0.000436

AC:

AN:

9176

East Asian (EAS)

AF:

0.00166

AC:

AN:

22286

South Asian (SAS)

AF:

0.00246

AC:

AN:

14232

European-Finnish (FIN)

AF:

0.000287

AC:

AN:

20938

Middle Eastern (MID)

AF:

0.00224

AC:

AN:

1338

European-Non Finnish (NFE)

AF:

0.000575

AC:

118

AN:

205206

Other (OTH)

AF:

0.000563

AC:

AN:

17770

⚠️ 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: 0.339

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000210

AC:

AN:

142674

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

AN XY:

69068

show subpopulations

African (AFR)

AF:

0.000308

AC:

AN:

38924

American (AMR)

AF:

0.000140

AC:

AN:

14326

Ashkenazi Jewish (ASJ)

AF:

0.000296

AC:

AN:

3378

East Asian (EAS)

AF:

0.000203

AC:

AN:

4932

South Asian (SAS)

AF:

0.000220

AC:

AN:

4544

European-Finnish (FIN)

AF:

0.000244

AC:

AN:

8208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

65264

Other (OTH)

AF:

0.00

AC:

AN:

1946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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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5-171392586-CTTTTTTT-CTT

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