Genetic Variant NRBP2:p.Arg449Trp (chr8-143836003-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178564.4(NRBP2):c.1345C>T(p.Arg449Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,577,178 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R449Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NRBP2
NM_178564.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

Publications

2 publications found

Variant links:

Genes affected

NRBP2 (HGNC:19339): (nuclear receptor binding protein 2) Predicted to enable protein serine/threonine kinase activity. Involved in negative regulation of macroautophagy. Predicted to be active in cytoplasm and endomembrane system. [provided by Alliance of Genome Resources, Apr 2022]

NRBP2 links:

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ACMG classification

Classification was made for transcript

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=0.26071793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRBP2	NM_178564.4 link	c.1345C>T	p.Arg449Trp	missense_variant	Exon 16 of 18	ENST00000442628.7	NP_848659.2	Q9NSY0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRBP2	ENST00000442628.7 link	c.1345C>T	p.Arg449Trp	missense_variant	Exon 16 of 18	2	NM_178564.4	ENSP00000414055.2		Q9NSY0-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000285

AC:

AN:

210810

AF XY:

0.0000346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000973

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000595

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000154

AC:

AN:

1424992

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

705584

show subpopulations

African (AFR)

AF:

0.0000944

AC:

AN:

31780

American (AMR)

AF:

0.0000724

AC:

AN:

41438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24130

East Asian (EAS)

AF:

0.00

AC:

AN:

38688

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

1093634

Other (OTH)

AF:

0.0000341

AC:

AN:

58724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41458

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000498

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1345C>T (p.R449W) alteration is located in exon 16 (coding exon 16) of the NRBP2 gene. This alteration results from a C to T substitution at nucleotide position 1345, causing the arginine (R) at amino acid position 449 to be replaced by a tryptophan (W). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.55

PhyloP100

1.4

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.19

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.017

Vest4

0.58

MVP

0.25

MPC

0.63

ClinPred

0.51

GERP RS

-6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.45

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over