NM_002520.7:c.353-110_353-107dupTTTT

Variant names:

• chr5-171392586-C-CTTTT
• rs34475806
• NM_002520.7:c.353-110_353-107dupTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002520.7(NPM1):​c.353-110_353-107dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 450,746 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: NPM1 NM_002520.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.94
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00177 (253/142666) while in subpopulation EAS AF = 0.0457 (225/4924). AF 95% confidence interval is 0.0408. There are 5 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 253 AD gene.

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.353-110_353-107dupTTTT		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.353-110_353-107dupTTTT		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.353-110_353-107dupTTTT		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.353-124_353-123insTTTT		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.353-124_353-123insTTTT		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.353-124_353-123insTTTT		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 253 AN: 142620 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000123

Gnomad OTH AF: 0.00103

GnomAD4 exome AF: 0.00111 AC: 341 AN: 308080 Hom.: 0 AF XY: 0.00113 AC XY: 180 AN XY: 159132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7546

American (AMR) AF: 0.000217 AC: 2 AN: 9200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9200

East Asian (EAS) AF: 0.0141 AC: 309 AN: 21918

South Asian (SAS) AF: 0.0000699 AC: 1 AN: 14304

European-Finnish (FIN) AF: 0.0000477 AC: 1 AN: 20980

Middle Eastern (MID) AF: 0.00149 AC: 2 AN: 1338

European-Non Finnish (NFE) AF: 0.0000680 AC: 14 AN: 205778

Other (OTH) AF: 0.000674 AC: 12 AN: 17816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00177 AC: 253 AN: 142666 Hom.: 5 Cov.: 0 AF XY: 0.00177 AC XY: 122 AN XY: 69064

African (AFR) AF: 0.000128 AC: 5 AN: 38924

American (AMR) AF: 0.000419 AC: 6 AN: 14326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3378

East Asian (EAS) AF: 0.0457 AC: 225 AN: 4924

South Asian (SAS) AF: 0.00154 AC: 7 AN: 4544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000123 AC: 8 AN: 65262

Other (OTH) AF: 0.00103 AC: 2 AN: 1946

Alfa AF: 0.00 Hom.: 448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34475806; hg19: chr5-170819590;