5-171392586-CTTTTTTT-CTTTTTTTTT

Variant names:

• chr5-171392586-C-CTT
• rs34475806
• NM_002520.7:c.353-108_353-107dupTT

Variant summary

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

The NM_002520.7(NPM1):​c.353-108_353-107dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 449,354 control chromosomes in the GnomAD database, including 21 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 0)
  • Exomes 𝑓: 0.010 (1 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 sas. GnomAd4 allele frequency = 0.0142 (2024/142644) while in subpopulation SAS AF = 0.0198 (90/4540). AF 95% confidence interval is 0.0165. There are 20 homozygotes in GnomAd4. There are 993 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2024 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.353-108_353-107dupTT		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.353-108_353-107dupTT		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.353-108_353-107dupTT		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_353-123insTT		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.353-124_353-123insTT		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.353-124_353-123insTT		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2023 AN: 142598 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0420

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0338

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0160

GnomAD4 exome AF: 0.0103 AC: 3165 AN: 306710 Hom.: 1 AF XY: 0.0102 AC XY: 1613 AN XY: 158398

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

African (AFR) AF: 0.00773 AC: 58 AN: 7504

American (AMR) AF: 0.00798 AC: 73 AN: 9152

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 124 AN: 9110

East Asian (EAS) AF: 0.000894 AC: 20 AN: 22366

South Asian (SAS) AF: 0.0103 AC: 147 AN: 14258

European-Finnish (FIN) AF: 0.0114 AC: 237 AN: 20860

Middle Eastern (MID) AF: 0.0225 AC: 30 AN: 1336

European-Non Finnish (NFE) AF: 0.0111 AC: 2276 AN: 204412

Other (OTH) AF: 0.0113 AC: 200 AN: 17712

⚠️ 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: 0.0142 AC: 2024 AN: 142644 Hom.: 20 Cov.: 0 AF XY: 0.0144 AC XY: 993 AN XY: 69052

African (AFR) AF: 0.0118 AC: 459 AN: 38918

American (AMR) AF: 0.0113 AC: 162 AN: 14328

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 78 AN: 3378

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4932

South Asian (SAS) AF: 0.0198 AC: 90 AN: 4540

European-Finnish (FIN) AF: 0.0134 AC: 110 AN: 8206

Middle Eastern (MID) AF: 0.0294 AC: 8 AN: 272

European-Non Finnish (NFE) AF: 0.0160 AC: 1047 AN: 65246

Other (OTH) AF: 0.0165 AC: 32 AN: 1944

Alfa AF: 0.00964 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

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

Other links and lift over

dbSNP: rs34475806; hg19: chr5-170819590;