NM_002520.7:c.353-109_353-107delTTT

Variant names:

• chr5-171392586-CTTT-C
• rs34475806
• NM_002520.7:c.353-109_353-107delTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002520.7(NPM1):​c.353-109_353-107delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 449,836 control chromosomes in the GnomAD database, including 16,249 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (9811 hom., cov: 0)
  • Exomes 𝑓: 0.35 (6438 hom.)
• Consequence: NPM1 NM_002520.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.718
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 5-171392586-CTTT-C is Benign according to our data. Variant chr5-171392586-CTTT-C is described in ClinVar as Benign. ClinVar VariationId is 1277189.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 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.353-109_353-107delTTT		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.353-109_353-107delTTT		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.353-109_353-107delTTT		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.353-123_353-121delTTT		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.353-123_353-121delTTT		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.353-123_353-121delTTT		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.375 AC: 53479 AN: 142548 Hom.: 9804 Cov.: 0

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.345 AC: 106148 AN: 307242 Hom.: 6438 AF XY: 0.347 AC XY: 55131 AN XY: 158688

African (AFR) AF: 0.281 AC: 2097 AN: 7464

American (AMR) AF: 0.349 AC: 3195 AN: 9158

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 3278 AN: 9176

East Asian (EAS) AF: 0.430 AC: 9607 AN: 22324

South Asian (SAS) AF: 0.406 AC: 5785 AN: 14234

European-Finnish (FIN) AF: 0.325 AC: 6778 AN: 20880

Middle Eastern (MID) AF: 0.324 AC: 429 AN: 1326

European-Non Finnish (NFE) AF: 0.337 AC: 69011 AN: 204924

Other (OTH) AF: 0.336 AC: 5968 AN: 17756

GnomAD4 genome AF: 0.375 AC: 53505 AN: 142594 Hom.: 9811 Cov.: 0 AF XY: 0.377 AC XY: 26018 AN XY: 69012

African (AFR) AF: 0.294 AC: 11418 AN: 38886

American (AMR) AF: 0.405 AC: 5801 AN: 14316

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1451 AN: 3378

East Asian (EAS) AF: 0.557 AC: 2747 AN: 4930

South Asian (SAS) AF: 0.475 AC: 2156 AN: 4540

European-Finnish (FIN) AF: 0.379 AC: 3108 AN: 8204

Middle Eastern (MID) AF: 0.331 AC: 90 AN: 272

European-Non Finnish (NFE) AF: 0.391 AC: 25482 AN: 65244

Other (OTH) AF: 0.409 AC: 796 AN: 1944

Alfa AF: 0.285 Hom.: 448

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
PhyloP100		0.72
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: rs34475806; hg19: chr5-170819590;