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GeneBe

3-128650607-C-T

Variant summary

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

The NM_002950.4(RPN1):c.194G>A(p.Arg65Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,550,374 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: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RPN1
NM_002950.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71
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=0.20378631).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPN1NM_002950.4 linkuse as main transcriptc.194G>A p.Arg65Gln missense_variant 1/10 ENST00000296255.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPN1ENST00000296255.8 linkuse as main transcriptc.194G>A p.Arg65Gln missense_variant 1/101 NM_002950.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000132
AC:
2
AN:
151878
Hom.:
0
AF XY:
0.0000124
AC XY:
1
AN XY:
80884
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:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000175
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000179
AC:
25
AN:
1398186
Hom.:
0
Cov.:
32
AF XY:
0.0000130
AC XY:
9
AN XY:
689732
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000558
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000195
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000487
Hom.:
0

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 GeneticsNov 29, 2023The c.194G>A (p.R65Q) alteration is located in exon 1 (coding exon 1) of the RPN1 gene. This alteration results from a G to A substitution at nucleotide position 194, causing the arginine (R) at amino acid position 65 to be replaced by a glutamine (Q). 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
0.088
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.068
T
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.42
N
LIST_S2
Benign
0.82
T
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
0.22
N
REVEL
Benign
0.032
Sift
Benign
0.31
T
Sift4G
Benign
0.58
T
Polyphen
0.14
B
Vest4
0.30
MutPred
0.62
Gain of glycosylation at T63 (P = 0.0182);
MVP
0.14
MPC
0.34
ClinPred
0.15
T
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.093
gMVP
0.44

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: rs376842979; hg19: chr3-128369450; API