rs3830035

Variant names:

• chr5-171392883-G-A
• rs3830035
• NM_002520.7:c.460-31G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002520.7(NPM1):​c.460-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,606,498 control chromosomes in the GnomAD database, including 121,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12426 hom., cov: 31)
  • Exomes 𝑓: 0.38 (109441 hom.)
• Consequence: NPM1 NM_002520.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0830
• Publications: 14 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-171392883-G-A is Benign according to our data. Variant chr5-171392883-G-A is described in ClinVar as Benign. ClinVar VariationId is 1275969.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPM1	NM_002520.7	MANE Select	c.460-31G>A		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.460-31G>A		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.460-31G>A		intron	N/A	NP_954654.1	P06748-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPM1	ENST00000296930.10	TSL:1 MANE Select	c.460-31G>A		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.460-31G>A		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.460-31G>A		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61352 AN: 151742 Hom.: 12404 Cov.: 31

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.415

GnomAD2 exomes AF: 0.412 AC: 103312 AN: 250982 AF XY: 0.414

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.545

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.383

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.384 AC: 558643 AN: 1454638 Hom.: 109441 Cov.: 34 AF XY: 0.387 AC XY: 280431 AN XY: 724032

African (AFR) AF: 0.418 AC: 13938 AN: 33314

American (AMR) AF: 0.405 AC: 18077 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11016 AN: 26076

East Asian (EAS) AF: 0.544 AC: 21583 AN: 39656

South Asian (SAS) AF: 0.472 AC: 40565 AN: 86004

European-Finnish (FIN) AF: 0.368 AC: 19664 AN: 53406

Middle Eastern (MID) AF: 0.389 AC: 2236 AN: 5754

European-Non Finnish (NFE) AF: 0.369 AC: 407452 AN: 1105612

Other (OTH) AF: 0.401 AC: 24112 AN: 60140

GnomAD4 genome AF: 0.404 AC: 61419 AN: 151860 Hom.: 12426 Cov.: 31 AF XY: 0.405 AC XY: 30049 AN XY: 74200

African (AFR) AF: 0.418 AC: 17283 AN: 41394

American (AMR) AF: 0.406 AC: 6200 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1476 AN: 3470

East Asian (EAS) AF: 0.549 AC: 2830 AN: 5154

South Asian (SAS) AF: 0.487 AC: 2345 AN: 4816

European-Finnish (FIN) AF: 0.365 AC: 3833 AN: 10514

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26030 AN: 67956

Other (OTH) AF: 0.412 AC: 865 AN: 2100

Alfa AF: 0.402 Hom.: 2790

Bravo AF: 0.407

Asia WGS AF: 0.458 AC: 1596 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.72
PhyloP100		-0.083
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs3830035; hg19: chr5-170819887; COSMIC: COSV51543174; COSMIC: COSV51543174;