chr5-171392785-C-G

Variant names:

• chr5-171392785-C-G
• rs375558588
• NM_002520.7:c.428C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002520.7(NPM1):​c.428C>G​(p.Ser143Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NPM1 NM_002520.7 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.90
• 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: G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2663169).
• BS2: High AC in GnomAdExome4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPM1	NM_002520.7	MANE Select	c.428C>G	p.Ser143Cys	missense	Exon 5 of 11	NP_002511.1
	NPM1	NM_001355006.2		c.428C>G	p.Ser143Cys	missense	Exon 6 of 12	NP_001341935.1
	NPM1	NM_199185.4		c.428C>G	p.Ser143Cys	missense	Exon 5 of 10	NP_954654.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPM1	ENST00000296930.10	TSL:1 MANE Select	c.428C>G	p.Ser143Cys	missense	Exon 5 of 11	ENSP00000296930.5
	NPM1	ENST00000517671.5	TSL:1	c.428C>G	p.Ser143Cys	missense	Exon 6 of 12	ENSP00000428755.1
	NPM1	ENST00000351986.10	TSL:1	c.428C>G	p.Ser143Cys	missense	Exon 5 of 10	ENSP00000341168.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250836 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461608 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111778

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.97
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.23
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.060	T
Polyphen		0.21	B
Vest4		0.28
MVP		0.46
MPC		1.5
ClinPred		0.59	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.058
Mutation Taster		=59/41	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: rs375558588; hg19: chr5-170819789;