Genetic Variant NUPR1:p.Arg82His (chr16-28538023-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012385.3(NUPR1):c.245G>A(p.Arg82His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

NUPR1
NM_012385.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

Variant links:

Genes affected

NUPR1 (HGNC:29990): (nuclear protein 1, transcriptional regulator) Enables DNA binding activity and transcription coactivator activity. Involved in several processes, including regulation of cellular catabolic process; regulation of generation of precursor metabolites and energy; and regulation of programmed cell death. Acts upstream of or within negative regulation of cell cycle. Located in intercellular bridge; nucleoplasm; and perinuclear region of cytoplasm. Part of protein-DNA complex. [provided by Alliance of Genome Resources, Apr 2022]

NUPR1 links:

ENSG00000289754 (HGNC:):

ENSG00000289754 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13363338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUPR1	NM_012385.3 link	c.245G>A	p.Arg82His	missense_variant	Exon 2 of 3	ENST00000324873.8	NP_036517.1	O60356-1A0A024QZC4
NUPR1	NM_001042483.2 link	c.299G>A	p.Arg100His	missense_variant	Exon 2 of 3		NP_001035948.1	O60356-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUPR1	ENST00000324873.8 link	c.245G>A	p.Arg82His	missense_variant	Exon 2 of 3	1	NM_012385.3	ENSP00000315559.7		O60356-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250462

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460428

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726392

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.299G>A (p.R100H) alteration is located in exon 2 (coding exon 2) of the NUPR1 gene. This alteration results from a G to A substitution at nucleotide position 299, causing the arginine (R) at amino acid position 100 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.87

N;N

REVEL

Benign

0.047

Sift

Benign

0.14

T;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.80

P;.

Vest4

0.13

MVP

0.42

MPC

0.36

ClinPred

0.86

GERP RS

1.3

Varity_R

0.031

gMVP

0.10

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over