Genetic Variant NPM1:c.525-39A>G (chr5-171400114-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002520.7(NPM1):c.525-39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,232,158 control chromosomes in the GnomAD database, including 95,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.40 ( 12275 hom., cov: 32)

Exomes 𝑓: 0.39 ( 82839 hom. )

Consequence

NPM1
NM_002520.7 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.38

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 5-171400114-A-G is Benign according to our data. Variant chr5-171400114-A-G is described in ClinVar as [Benign]. Clinvar id is 1290345.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPM1	NM_002520.7 link	c.525-39A>G		intron_variant	Intron 6 of 10	ENST00000296930.10	NP_002511.1	P06748-1A0A0S2Z491

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPM1	ENST00000296930.10 link	c.525-39A>G		intron_variant	Intron 6 of 10	1	NM_002520.7	ENSP00000296930.5		P06748-1

Frequencies

GnomAD3 genomes

AF:

0.403

AC:

61075

AN:

151564

Hom.:

12252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.416

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.425

Gnomad EAS

AF:

0.546

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.312

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.411

AC:

99668

AN:

242624

AF XY:

0.413

show subpopulations

Gnomad AFR exome

AF:

0.426

Gnomad AMR exome

AF:

0.400

Gnomad ASJ exome

AF:

0.424

Gnomad EAS exome

AF:

0.543

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.381

Gnomad OTH exome

AF:

0.395

GnomAD4 exome

AF:

0.386

AC:

416997

AN:

1080474

Hom.:

82839

Cov.:

AF XY:

0.390

AC XY:

216308

AN XY:

554914

show subpopulations

Gnomad4 AFR exome

AF:

0.416

AC:

10840

AN:

26052

Gnomad4 AMR exome

AF:

0.404

AC:

17648

AN:

43720

Gnomad4 ASJ exome

AF:

0.421

AC:

9942

AN:

23588

Gnomad4 EAS exome

AF:

0.545

AC:

20608

AN:

37812

Gnomad4 SAS exome

AF:

0.470

AC:

36595

AN:

77930

Gnomad4 FIN exome

AF:

0.368

AC:

19187

AN:

52128

Gnomad4 NFE exome

AF:

0.367

AC:

281184

AN:

766520

Gnomad4 Remaining exome

AF:

0.400

AC:

19062

AN:

47698

Heterozygous variant carriers

12763

25526

38288

51051

63814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

7388

14776

22164

29552

36940

<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:

0.403

AC:

61144

AN:

151684

Hom.:

12275

Cov.:

AF XY:

0.403

AC XY:

29899

AN XY:

74104

show subpopulations

Gnomad4 AFR

AF:

0.416

AC:

0.415989

AN:

0.415989

Gnomad4 AMR

AF:

0.405

AC:

0.405186

AN:

0.405186

Gnomad4 ASJ

AF:

0.425

AC:

0.424697

AN:

0.424697

Gnomad4 EAS

AF:

0.547

AC:

0.546765

AN:

0.546765

Gnomad4 SAS

AF:

0.487

AC:

0.487126

AN:

0.487126

Gnomad4 FIN

AF:

0.363

AC:

0.362505

AN:

0.362505

Gnomad4 NFE

AF:

0.382

AC:

0.381837

AN:

0.381837

Gnomad4 OTH

AF:

0.412

AC:

0.412239

AN:

0.412239

Heterozygous variant carriers

1909

3818

5726

7635

9544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.409

Hom.:

3610

Bravo

AF:

0.407

Asia WGS

AF:

0.459

AC:

1599

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

7.3

DANN

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over