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GeneBe

3-128622232-C-G

Variant summary

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

The NM_002950.4(RPN1):c.1573G>C(p.Ala525Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,614,214 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 (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

RPN1
NM_002950.4 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73
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=0.09835991).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPN1NM_002950.4 linkuse as main transcriptc.1573G>C p.Ala525Pro missense_variant 9/10 ENST00000296255.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPN1ENST00000296255.8 linkuse as main transcriptc.1573G>C p.Ala525Pro missense_variant 9/101 NM_002950.4 P1
RPN1ENST00000497289.5 linkuse as main transcriptc.1057G>C p.Ala353Pro missense_variant 9/102

Frequencies

GnomAD3 genomes
AF:
0.000190
AC:
29
AN:
152232
Hom.:
0
Cov.:
33
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:
0.000282
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000266
AC:
67
AN:
251450
Hom.:
0
AF XY:
0.000265
AC XY:
36
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000785
Gnomad NFE exome
AF:
0.000334
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000205
AC:
299
AN:
1461864
Hom.:
0
Cov.:
33
AF XY:
0.000212
AC XY:
154
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000497
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000786
Gnomad4 NFE exome
AF:
0.000209
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152350
Hom.:
0
Cov.:
33
AF XY:
0.000215
AC XY:
16
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000365
Hom.:
0
Bravo
AF:
0.000128
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

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 GeneticsJan 23, 2023The c.1573G>C (p.A525P) alteration is located in exon 9 (coding exon 9) of the RPN1 gene. This alteration results from a G to C substitution at nucleotide position 1573, causing the alanine (A) at amino acid position 525 to be replaced by a proline (P). 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
Pathogenic
0.60
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
T;T
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.098
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.1
M;.
MutationTaster
Benign
0.91
D;D
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.12
Sift
Benign
0.17
T;T
Sift4G
Benign
0.27
T;T
Polyphen
0.74
P;.
Vest4
0.51
MVP
0.26
MPC
0.58
ClinPred
0.065
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.52
gMVP
0.57

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: rs201108570; hg19: chr3-128341075; COSMIC: COSV56190652; COSMIC: COSV56190652; API