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GeneBe

5-171387987-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_002520.7(NPM1):c.39G>A(p.Arg13=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,489,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00065 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

NPM1
NM_002520.7 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.27
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.19).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-171387987-G-A is Benign according to our data. Variant chr5-171387987-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3033346.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=2.28 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 96 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPM1NM_002520.7 linkuse as main transcriptc.39G>A p.Arg13= synonymous_variant 1/11 ENST00000296930.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPM1ENST00000296930.10 linkuse as main transcriptc.39G>A p.Arg13= synonymous_variant 1/111 NM_002520.7 P1P06748-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000648
AC:
96
AN:
148090
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000245
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000201
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:
0.00124
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000558
AC:
139
AN:
248942
Hom.:
0
AF XY:
0.000584
AC XY:
79
AN XY:
135376
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000277
Gnomad NFE exome
AF:
0.00114
Gnomad OTH exome
AF:
0.000659
GnomAD4 exome
AF:
0.00106
AC:
1428
AN:
1341388
Hom.:
0
Cov.:
32
AF XY:
0.00100
AC XY:
668
AN XY:
666724
show subpopulations
Gnomad4 AFR exome
AF:
0.000134
Gnomad4 AMR exome
AF:
0.0000970
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000262
Gnomad4 NFE exome
AF:
0.00133
Gnomad4 OTH exome
AF:
0.000632
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000654
AC:
97
AN:
148244
Hom.:
1
Cov.:
31
AF XY:
0.000497
AC XY:
36
AN XY:
72448
show subpopulations
Gnomad4 AFR
AF:
0.000244
Gnomad4 AMR
AF:
0.000201
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00126
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000916
Hom.:
0
Bravo
AF:
0.000552
EpiCase
AF:
0.00115
EpiControl
AF:
0.000889

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

NPM1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 10, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.19
Cadd
Benign
16
Dann
Benign
0.95
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7

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.

Other links and lift over

dbSNP: rs142254256; hg19: chr5-170814991; API