rs6555952

Variant names:

• chr5-171400111-C-A
• rs6555952
• NM_002520.7:c.525-42C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-171400111-C-A
• chr5-171400111-C-G

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.525-42C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,187,012 control chromosomes in the GnomAD database, including 92,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12271 hom., cov: 32)
  • Exomes 𝑓: 0.39 (79812 hom.)
• Consequence: NPM1 NM_002520.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.77
• Publications: 7 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=-0.9).
• BP6: Variant 5-171400111-C-A is Benign according to our data. Variant chr5-171400111-C-A is described in ClinVar as Benign. ClinVar VariationId is 1226494.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.

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.525-42C>A		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.525-42C>A		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.525-42C>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.525-42C>A		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.525-42C>A		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.525-42C>A		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61060 AN: 151446 Hom.: 12248 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.415

GnomAD2 exomes AF: 0.411 AC: 99260 AN: 241676 AF XY: 0.413

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.388 AC: 402239 AN: 1035450 Hom.: 79812 Cov.: 14 AF XY: 0.392 AC XY: 209354 AN XY: 533748

African (AFR) AF: 0.421 AC: 10571 AN: 25104

American (AMR) AF: 0.405 AC: 17568 AN: 43386

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 9844 AN: 23104

East Asian (EAS) AF: 0.549 AC: 20526 AN: 37404

South Asian (SAS) AF: 0.470 AC: 36213 AN: 77088

European-Finnish (FIN) AF: 0.373 AC: 19133 AN: 51244

Middle Eastern (MID) AF: 0.387 AC: 1908 AN: 4928

European-Non Finnish (NFE) AF: 0.368 AC: 267943 AN: 727210

Other (OTH) AF: 0.403 AC: 18533 AN: 45982

GnomAD4 genome AF: 0.403 AC: 61129 AN: 151562 Hom.: 12271 Cov.: 32 AF XY: 0.404 AC XY: 29893 AN XY: 74052

African (AFR) AF: 0.416 AC: 17191 AN: 41304

American (AMR) AF: 0.406 AC: 6186 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1472 AN: 3466

East Asian (EAS) AF: 0.547 AC: 2800 AN: 5122

South Asian (SAS) AF: 0.488 AC: 2346 AN: 4804

European-Finnish (FIN) AF: 0.363 AC: 3811 AN: 10508

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.382 AC: 25907 AN: 67808

Other (OTH) AF: 0.412 AC: 867 AN: 2104

Alfa AF: 0.337 Hom.: 1810

Bravo AF: 0.407

Asia WGS AF: 0.459 AC: 1599 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	-0.90
CADD	Benign	0.0080
DANN	Benign	0.65
PhyloP100		-2.8
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

Other links and lift over

dbSNP: rs6555952; hg19: chr5-170827115; COSMIC: COSV51545512; COSMIC: COSV51545512;