5-171392586-CTTTTTTT-CTTTTTT

Variant names:

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

Variant summary

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

The NM_002520.7(NPM1):​c.353-107delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 444,974 control chromosomes in the GnomAD database, including 18 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 0)
  • Exomes 𝑓: 0.075 (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 afr. GnomAd4 allele frequency = 0.0102 (1450/142630) while in subpopulation AFR AF = 0.0292 (1136/38904). AF 95% confidence interval is 0.0278. There are 18 homozygotes in GnomAd4. There are 652 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1450 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.353-107delT		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.353-107delT		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.353-107delT		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.353-123delT		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.353-123delT		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.353-123delT		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1441 AN: 142586 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.00227

Gnomad AMR AF: 0.00363

Gnomad ASJ AF: 0.000888

Gnomad EAS AF: 0.00243

Gnomad SAS AF: 0.000875

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00239

Gnomad OTH AF: 0.00515

GnomAD4 exome AF: 0.0750 AC: 22685 AN: 302344 Hom.: 0 AF XY: 0.0742 AC XY: 11592 AN XY: 156124

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

African (AFR) AF: 0.0986 AC: 727 AN: 7372

American (AMR) AF: 0.0837 AC: 753 AN: 8996

Ashkenazi Jewish (ASJ) AF: 0.0669 AC: 604 AN: 9028

East Asian (EAS) AF: 0.0608 AC: 1332 AN: 21906

South Asian (SAS) AF: 0.0446 AC: 631 AN: 14162

European-Finnish (FIN) AF: 0.0830 AC: 1709 AN: 20578

Middle Eastern (MID) AF: 0.0720 AC: 95 AN: 1320

European-Non Finnish (NFE) AF: 0.0766 AC: 15449 AN: 201556

Other (OTH) AF: 0.0795 AC: 1385 AN: 17426

⚠️ 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: 0.0102 AC: 1450 AN: 142630 Hom.: 18 Cov.: 0 AF XY: 0.00944 AC XY: 652 AN XY: 69054

African (AFR) AF: 0.0292 AC: 1136 AN: 38904

American (AMR) AF: 0.00384 AC: 55 AN: 14324

Ashkenazi Jewish (ASJ) AF: 0.000888 AC: 3 AN: 3378

East Asian (EAS) AF: 0.00243 AC: 12 AN: 4932

South Asian (SAS) AF: 0.000660 AC: 3 AN: 4544

European-Finnish (FIN) AF: 0.00877 AC: 72 AN: 8208

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.00239 AC: 156 AN: 65244

Other (OTH) AF: 0.00514 AC: 10 AN: 1944

Alfa AF: 0.00252 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

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;