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GeneBe

3-128625535-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PP3_StrongBP6_ModerateBS2

The NM_002950.4(RPN1):c.1394A>G(p.Lys465Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000699 in 1,613,576 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0038 ( 6 hom., cov: 31)
Exomes 𝑓: 0.00038 ( 4 hom. )

Consequence

RPN1
NM_002950.4 missense, splice_region

Scores

9
9
Splicing: ADA: 1.000
2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.54
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 Likely_benign. Variant got -2 ACMG points.

PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BP6
Variant 3-128625535-T-C is Benign according to our data. Variant chr3-128625535-T-C is described in ClinVar as [Benign]. Clinvar id is 713300.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPN1NM_002950.4 linkuse as main transcriptc.1394A>G p.Lys465Arg missense_variant, splice_region_variant 8/10 ENST00000296255.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPN1ENST00000296255.8 linkuse as main transcriptc.1394A>G p.Lys465Arg missense_variant, splice_region_variant 8/101 NM_002950.4 P1
RPN1ENST00000497289.5 linkuse as main transcriptc.878A>G p.Lys293Arg missense_variant, splice_region_variant 8/102

Frequencies

GnomAD3 genomes
AF:
0.00375
AC:
570
AN:
151946
Hom.:
6
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0131
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00131
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:
0.0000735
Gnomad OTH
AF:
0.000962
GnomAD3 exomes
AF:
0.000958
AC:
240
AN:
250454
Hom.:
3
AF XY:
0.000672
AC XY:
91
AN XY:
135380
show subpopulations
Gnomad AFR exome
AF:
0.0136
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000886
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.000379
AC:
554
AN:
1461512
Hom.:
4
Cov.:
31
AF XY:
0.000333
AC XY:
242
AN XY:
727070
show subpopulations
Gnomad4 AFR exome
AF:
0.0139
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.000861
GnomAD4 genome
AF:
0.00377
AC:
574
AN:
152064
Hom.:
6
Cov.:
31
AF XY:
0.00352
AC XY:
262
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0132
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000951
Alfa
AF:
0.000654
Hom.:
1
Bravo
AF:
0.00440
ESP6500AA
AF:
0.0168
AC:
74
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00123
AC:
149
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeApr 30, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.22
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T;T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.93
D;D
MetaRNN
Benign
0.010
T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.4
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.23
Sift
Uncertain
0.011
D;T
Sift4G
Uncertain
0.055
T;T
Polyphen
0.88
P;.
Vest4
0.72
MVP
0.40
MPC
0.44
ClinPred
0.040
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.56
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.060
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: rs146757242; hg19: chr3-128344378; API