rs34351976

Variant names:

• chr5-171410729-CT-C
• rs34351976
• NM_002520.7:c.*165delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_002520.7(NPM1):​c.*165delT variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.326 in 509,706 control chromosomes in the GnomAD database, including 29,164 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6957 hom., cov: 21)
  • Exomes 𝑓: 0.35 (22207 hom.)
• Consequence: NPM1 NM_002520.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83
• Publications: 6 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: G2P, Orphanet
• bone marrow failure syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 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.*165delT		3_prime_UTR	Exon 11 of 11	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.*165delT		3_prime_UTR	Exon 12 of 12	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.*165delT		3_prime_UTR	Exon 10 of 10	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.*165delT		3_prime_UTR	Exon 11 of 11	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.*165delT		3_prime_UTR	Exon 12 of 12	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.*165delT		3_prime_UTR	Exon 10 of 10	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42762 AN: 151790 Hom.: 6956 Cov.: 21

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.316

GnomAD4 exome AF: 0.345 AC: 123500 AN: 357798 Hom.: 22207 Cov.: 0 AF XY: 0.348 AC XY: 65400 AN XY: 188166

African (AFR) AF: 0.117 AC: 1115 AN: 9556

American (AMR) AF: 0.218 AC: 2399 AN: 10988

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 4345 AN: 11732

East Asian (EAS) AF: 0.427 AC: 11492 AN: 26918

South Asian (SAS) AF: 0.351 AC: 9024 AN: 25730

European-Finnish (FIN) AF: 0.359 AC: 9349 AN: 26058

Middle Eastern (MID) AF: 0.336 AC: 576 AN: 1712

European-Non Finnish (NFE) AF: 0.349 AC: 78000 AN: 223352

Other (OTH) AF: 0.331 AC: 7200 AN: 21752

GnomAD4 genome AF: 0.281 AC: 42761 AN: 151908 Hom.: 6957 Cov.: 21 AF XY: 0.281 AC XY: 20842 AN XY: 74232

African (AFR) AF: 0.114 AC: 4742 AN: 41462

American (AMR) AF: 0.237 AC: 3615 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1294 AN: 3466

East Asian (EAS) AF: 0.429 AC: 2212 AN: 5152

South Asian (SAS) AF: 0.373 AC: 1795 AN: 4810

European-Finnish (FIN) AF: 0.354 AC: 3723 AN: 10512

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24172 AN: 67916

Other (OTH) AF: 0.313 AC: 661 AN: 2112

Alfa AF: 0.206 Hom.: 530

Bravo AF: 0.264

Asia WGS AF: 0.322 AC: 1120 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34351976;

hg19: chr5-170837733;

COSMIC: COSV51543200;

COSMIC: COSV51543200;