Genetic Variant NPM1:c.353-109_353-107dupTTT (chr5-171392586-C-CTTT) – 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.353-109_353-107dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 450,752 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 0.00017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00089 ( 0 hom. )

Consequence

NPM1
NM_002520.7 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.94

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 24 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.353-109_353-107dupTTT	intron	N/A	NP_002511.1	A0A0S2Z491
NPM1	NM_001355006.2		c.353-109_353-107dupTTT	intron	N/A	NP_001341935.1	A0A0S2Z491
NPM1	NM_199185.4		c.353-109_353-107dupTTT	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.353-124_353-123insTTT	intron	N/A	ENSP00000296930.5	P06748-1
NPM1	ENST00000517671.5	TSL:1	c.353-124_353-123insTTT	intron	N/A	ENSP00000428755.1	P06748-1
NPM1	ENST00000351986.10	TSL:1	c.353-124_353-123insTTT	intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes

AF:

0.000168

AC:

AN:

142628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000515

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00101

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00158

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000613

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000893

AC:

275

AN:

308078

Hom.:

AF XY:

0.000792

AC XY:

126

AN XY:

159168

show subpopulations

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

African (AFR)

AF:

0.000265

AC:

AN:

7540

American (AMR)

AF:

0.000544

AC:

AN:

9198

Ashkenazi Jewish (ASJ)

AF:

0.000435

AC:

AN:

9192

East Asian (EAS)

AF:

0.00525

AC:

116

AN:

22088

South Asian (SAS)

AF:

0.00105

AC:

AN:

14302

European-Finnish (FIN)

AF:

0.000763

AC:

AN:

20974

Middle Eastern (MID)

AF:

0.000747

AC:

AN:

1338

European-Non Finnish (NFE)

AF:

0.000530

AC:

109

AN:

205636

Other (OTH)

AF:

0.000393

AC:

AN:

17810

⚠️ 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: 0.283

Heterozygous variant carriers

101

126

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:

0.000168

AC:

AN:

142674

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

AN XY:

69070

show subpopulations

African (AFR)

AF:

0.0000514

AC:

AN:

38924

American (AMR)

AF:

0.00

AC:

AN:

14326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00101

AC:

AN:

4932

South Asian (SAS)

AF:

0.00

AC:

AN:

4544

European-Finnish (FIN)

AF:

0.00158

AC:

AN:

8208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000613

AC:

AN:

65264

Other (OTH)

AF:

0.00

AC:

AN:

1946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

-2.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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5-171392586-CTTTTTTT-CTTTTTTTTTT

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