5-171392586-CTT-C

Variant names:

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

Variant summary

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

The NM_002520.7(NPM1):​c.353-108_353-107delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 444,062 control chromosomes in the GnomAD database, including 355 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.038 (346 hom., cov: 0)
  • Exomes 𝑓: 0.023 (9 hom.)
• Consequence: NPM1 NM_002520.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• 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 (AFR) allele frequency at 95% confidence interval = 0.125 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.353-108_353-107delTT		intron	N/A	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.353-108_353-107delTT		intron	N/A	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.353-108_353-107delTT		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.353-123_353-122delTT		intron	N/A	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.353-123_353-122delTT		intron	N/A	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.353-123_353-122delTT		intron	N/A	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5408 AN: 142574 Hom.: 341 Cov.: 0

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.00131

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00676

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0247

GnomAD4 exome AF: 0.0226 AC: 6801 AN: 301442 Hom.: 9 AF XY: 0.0219 AC XY: 3417 AN XY: 155782

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

African (AFR) AF: 0.121 AC: 897 AN: 7390

American (AMR) AF: 0.0334 AC: 299 AN: 8950

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 154 AN: 8956

East Asian (EAS) AF: 0.0185 AC: 401 AN: 21686

South Asian (SAS) AF: 0.0232 AC: 327 AN: 14088

European-Finnish (FIN) AF: 0.0240 AC: 491 AN: 20490

Middle Eastern (MID) AF: 0.0247 AC: 32 AN: 1298

European-Non Finnish (NFE) AF: 0.0183 AC: 3674 AN: 201252

Other (OTH) AF: 0.0303 AC: 526 AN: 17332

⚠️ 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: 0.0381 AC: 5428 AN: 142620 Hom.: 346 Cov.: 0 AF XY: 0.0379 AC XY: 2619 AN XY: 69040

African (AFR) AF: 0.128 AC: 4964 AN: 38900

American (AMR) AF: 0.0156 AC: 223 AN: 14322

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3378

East Asian (EAS) AF: 0.00101 AC: 5 AN: 4932

South Asian (SAS) AF: 0.00132 AC: 6 AN: 4544

European-Finnish (FIN) AF: 0.0118 AC: 97 AN: 8196

Middle Eastern (MID) AF: 0.00735 AC: 2 AN: 272

European-Non Finnish (NFE) AF: 0.00126 AC: 82 AN: 65250

Other (OTH) AF: 0.0247 AC: 48 AN: 1946

Alfa AF: 0.00104 Hom.: 448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.46
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;