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GeneBe

3-128644979-T-C

Variant summary

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

The NM_002950.4(RPN1):c.266A>G(p.Lys89Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000926 in 1,403,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000093 ( 0 hom. )

Consequence

RPN1
NM_002950.4 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.20
Variant links:
Genes affected
RPN1 (HGNC:10381): (ribophorin I) This gene encodes a type I integral membrane protein found only in the rough endoplasmic reticulum. The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains. This protein forms part of the regulatory subunit of the 26S proteasome and may mediate binding of ubiquitin-like domains to this proteasome. [provided by RefSeq, Jul 2008]

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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=0.22504929).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPN1NM_002950.4 linkuse as main transcriptc.266A>G p.Lys89Arg missense_variant 2/10 ENST00000296255.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPN1ENST00000296255.8 linkuse as main transcriptc.266A>G p.Lys89Arg missense_variant 2/101 NM_002950.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250814
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135572
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000926
AC:
13
AN:
1403670
Hom.:
0
Cov.:
24
AF XY:
0.00000855
AC XY:
6
AN XY:
701664
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000113
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 04, 2022The c.266A>G (p.K89R) alteration is located in exon 2 (coding exon 2) of the RPN1 gene. This alteration results from a A to G substitution at nucleotide position 266, causing the lysine (K) at amino acid position 89 to be replaced by an arginine (R). 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
0.082
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.085
Eigen_PC
Benign
0.059
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.057
Sift
Benign
0.097
T
Sift4G
Benign
0.36
T
Polyphen
0.063
B
Vest4
0.42
MutPred
0.46
Gain of sheet (P = 0.0028);
MVP
0.18
MPC
0.25
ClinPred
0.37
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.24
gMVP
0.55

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: rs1377173099; hg19: chr3-128363822; COSMIC: COSV56189960; COSMIC: COSV56189960; API