chr2-27441752-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013392.4(NRBP1):​c.1548C>A​(p.Asn516Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NRBP1
NM_013392.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19
Variant links:
Genes affected
NRBP1 (HGNC:7993): (nuclear receptor binding protein 1) Predicted to enable protein homodimerization activity. Involved in endoplasmic reticulum to Golgi vesicle-mediated transport. Located in endomembrane system. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05142209).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NRBP1NM_013392.4 linkc.1548C>A p.Asn516Lys missense_variant Exon 18 of 18 ENST00000379852.8 NP_037524.1 Q9UHY1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NRBP1ENST00000379852.8 linkc.1548C>A p.Asn516Lys missense_variant Exon 18 of 18 1 NM_013392.4 ENSP00000369181.3 Q9UHY1
NRBP1ENST00000379863.7 linkc.1572C>A p.Asn524Lys missense_variant Exon 19 of 19 5 ENSP00000369192.3 F8W6G1
NRBP1ENST00000233557.7 linkc.1548C>A p.Asn516Lys missense_variant Exon 19 of 19 2 ENSP00000233557.3 Q9UHY1
NRBP1ENST00000460499.5 linkn.2058C>A non_coding_transcript_exon_variant Exon 11 of 11 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251266
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461810
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 05, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1548C>A (p.N516K) alteration is located in exon 18 (coding exon 17) of the NRBP1 gene. This alteration results from a C to A substitution at nucleotide position 1548, causing the asparagine (N) at amino acid position 516 to be replaced by a lysine (K). 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
-0.44
T
BayesDel_noAF
Benign
-0.57
CADD
Uncertain
24
DANN
Benign
0.91
DEOGEN2
Benign
0.037
T;T;T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.072
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.75
.;T;T
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.051
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.0
L;L;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
0.47
N;N;N
REVEL
Benign
0.10
Sift
Benign
1.0
T;T;T
Sift4G
Benign
0.94
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.29
MutPred
0.18
.;.;Loss of ubiquitination at K525 (P = 0.0437);
MVP
0.38
MPC
0.74
ClinPred
0.13
T
GERP RS
5.6
Varity_R
0.22
gMVP
0.50

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.

Other links and lift over

dbSNP: rs746470640; hg19: chr2-27664619; API