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GeneBe

3-128632135-T-G

Variant summary

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

The NM_002950.4(RPN1):c.656A>C(p.Glu219Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,114 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 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RPN1
NM_002950.4 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.53
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, 0.808

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPN1NM_002950.4 linkuse as main transcriptc.656A>C p.Glu219Ala missense_variant 4/10 ENST00000296255.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPN1ENST00000296255.8 linkuse as main transcriptc.656A>C p.Glu219Ala missense_variant 4/101 NM_002950.4 P1
RPN1ENST00000497289.5 linkuse as main transcriptc.140A>C p.Glu47Ala missense_variant 4/102
RPN1ENST00000495462.5 linkuse as main transcriptn.552A>C non_coding_transcript_exon_variant 4/43

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251392
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
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:
0.00000137
AC:
2
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
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
AF:
0.00000657
AC:
1
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
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:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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 07, 2024The c.656A>C (p.E219A) alteration is located in exon 4 (coding exon 4) of the RPN1 gene. This alteration results from a A to C substitution at nucleotide position 656, causing the glutamic acid (E) at amino acid position 219 to be replaced by an alanine (A). 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
0.85
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
T;T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.053
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Pathogenic
3.0
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-6.0
D;D
REVEL
Uncertain
0.58
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.89
MutPred
0.67
Gain of glycosylation at Y218 (P = 0.0266);.;
MVP
0.45
MPC
1.0
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.74

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: rs752445372; hg19: chr3-128350978; API