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GeneBe

5-171392976-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_002520.7(NPM1):c.522A>G(p.Glu174=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,609,544 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 3 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 47 hom. )

Consequence

NPM1
NM_002520.7 splice_region, synonymous

Scores

2
Splicing: ADA: 0.001468
2

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.949
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 -12 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=-0.46).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-171392976-A-G is Benign according to our data. Variant chr5-171392976-A-G is described in ClinVar as [Benign]. Clinvar id is 2443194.Status of the report is no_assertion_criteria_provided, 0 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=0.949 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000788 (120/152318) while in subpopulation SAS AF= 0.0236 (114/4824). AF 95% confidence interval is 0.0201. There are 3 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
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 121 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPM1NM_002520.7 linkuse as main transcriptc.522A>G p.Glu174= splice_region_variant, synonymous_variant 6/11 ENST00000296930.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPM1ENST00000296930.10 linkuse as main transcriptc.522A>G p.Glu174= splice_region_variant, synonymous_variant 6/111 NM_002520.7 P1P06748-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000795
AC:
121
AN:
152200
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0238
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00299
AC:
737
AN:
246284
Hom.:
16
AF XY:
0.00396
AC XY:
529
AN XY:
133444
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.0238
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000182
Gnomad OTH exome
AF:
0.00116
GnomAD4 exome
AF:
0.00141
AC:
2058
AN:
1457226
Hom.:
47
Cov.:
32
AF XY:
0.00207
AC XY:
1503
AN XY:
725126
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000757
Gnomad4 SAS exome
AF:
0.0229
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00113
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000788
AC:
120
AN:
152318
Hom.:
3
Cov.:
33
AF XY:
0.00101
AC XY:
75
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0236
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000140
Asia WGS
AF:
0.00808
AC:
28
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoJun 06, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
Cadd
Benign
11
Dann
Benign
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0015
dbscSNV1_RF
Benign
0.030
SpliceAI score (max)
0.010
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: rs368269652; hg19: chr5-170819980; API