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GeneBe

3-128625978-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002950.4(RPN1):c.1171C>T(p.Arg391Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,611,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RPN1
NM_002950.4 missense

Scores

9
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.29
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPN1NM_002950.4 linkuse as main transcriptc.1171C>T p.Arg391Cys missense_variant 7/10 ENST00000296255.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPN1ENST00000296255.8 linkuse as main transcriptc.1171C>T p.Arg391Cys missense_variant 7/101 NM_002950.4 P1
RPN1ENST00000497289.5 linkuse as main transcriptc.655C>T p.Arg219Cys missense_variant 7/102
RPN1ENST00000490166.1 linkuse as main transcriptn.569C>T non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.0000363
AC:
9
AN:
247606
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
133862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000598
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000275
Gnomad SAS exome
AF:
0.0000334
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000890
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000206
AC:
30
AN:
1459328
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
725950
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000684
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000816
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152088
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000480
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5

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 GeneticsMar 17, 2023The c.1171C>T (p.R391C) alteration is located in exon 7 (coding exon 7) of the RPN1 gene. This alteration results from a C to T substitution at nucleotide position 1171, causing the arginine (R) at amino acid position 391 to be replaced by a cysteine (C). 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
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.46
T;T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.032
D
MetaRNN
Pathogenic
0.76
D;D
MetaSVM
Uncertain
-0.070
T
MutationAssessor
Pathogenic
3.0
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-6.7
D;D
REVEL
Uncertain
0.39
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.84
MVP
0.54
MPC
0.94
ClinPred
0.89
D
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.84
gMVP
0.75

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

LitVar

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

Other links and lift over

dbSNP: rs149030563; hg19: chr3-128344821; API