5-171392586-CTTTTTTT-CTTTTTTTT

Variant names:

• chr5-171392586-C-CT
• rs34475806
• NM_002520.7:c.353-107dupT

Variant summary

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

The NM_002520.7(NPM1):​c.353-107dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 444,594 control chromosomes in the GnomAD database, including 1,368 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1331 hom., cov: 0)
  • Exomes 𝑓: 0.095 (37 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.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 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.353-107dupT		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.353-107dupT		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.353-107dupT		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_353-123insT		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.353-124_353-123insT		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.353-124_353-123insT		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 19320 AN: 142344 Hom.: 1334 Cov.: 0

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0786

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.00324

Gnomad SAS AF: 0.0761

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.243

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.0951 AC: 28740 AN: 302206 Hom.: 37 AF XY: 0.0942 AC XY: 14708 AN XY: 156064

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

African (AFR) AF: 0.0926 AC: 685 AN: 7396

American (AMR) AF: 0.0704 AC: 636 AN: 9034

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 950 AN: 8844

East Asian (EAS) AF: 0.0114 AC: 255 AN: 22340

South Asian (SAS) AF: 0.0494 AC: 699 AN: 14164

European-Finnish (FIN) AF: 0.115 AC: 2365 AN: 20522

Middle Eastern (MID) AF: 0.121 AC: 156 AN: 1290

European-Non Finnish (NFE) AF: 0.106 AC: 21251 AN: 201216

Other (OTH) AF: 0.100 AC: 1743 AN: 17400

⚠️ 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: 0.136 AC: 19307 AN: 142388 Hom.: 1331 Cov.: 0 AF XY: 0.132 AC XY: 9098 AN XY: 68904

African (AFR) AF: 0.130 AC: 5036 AN: 38846

American (AMR) AF: 0.103 AC: 1475 AN: 14294

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 556 AN: 3370

East Asian (EAS) AF: 0.00324 AC: 16 AN: 4932

South Asian (SAS) AF: 0.0752 AC: 341 AN: 4536

European-Finnish (FIN) AF: 0.147 AC: 1196 AN: 8148

Middle Eastern (MID) AF: 0.246 AC: 67 AN: 272

European-Non Finnish (NFE) AF: 0.158 AC: 10280 AN: 65170

Other (OTH) AF: 0.140 AC: 271 AN: 1942

Alfa AF: 0.0745 Hom.: 448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.9
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;