rs267600552

Variant names:

• chr5-171400160-G-A
• rs267600552
• NM_002520.7:c.532G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-171400160-G-A
• chr5-171400160-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002520.7(NPM1):​c.532G>A​(p.Asp178Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D178H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPM1 NM_002520.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22676879).

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.532G>A	p.Asp178Asn	missense	Exon 7 of 11	NP_002511.1	A0A0S2Z491
	NPM1	NM_001355006.2		c.532G>A	p.Asp178Asn	missense	Exon 8 of 12	NP_001341935.1	A0A0S2Z491
	NPM1	NM_199185.4		c.532G>A	p.Asp178Asn	missense	Exon 7 of 10	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.532G>A	p.Asp178Asn	missense	Exon 7 of 11	ENSP00000296930.5	P06748-1
	NPM1	ENST00000517671.5	TSL:1	c.532G>A	p.Asp178Asn	missense	Exon 8 of 12	ENSP00000428755.1	P06748-1
	NPM1	ENST00000351986.10	TSL:1	c.532G>A	p.Asp178Asn	missense	Exon 7 of 10	ENSP00000341168.6	P06748-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.079
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.015	D
Polyphen		0.016	B
Vest4		0.43
MutPred		0.36		Gain of relative solvent accessibility (P = 0.1571)
MVP		0.48
MPC		0.23
ClinPred		0.71	D
GERP RS		3.6
Varity_R		0.13
gMVP		0.027
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267600552; hg19: chr5-170827164;