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GeneBe

3-128632079-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2

The NM_002950.4(RPN1):c.712C>T(p.His238Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,170 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00073 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 24 hom. )

Consequence

RPN1
NM_002950.4 missense

Scores

12
4
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.02191469).
BS2
High Homozygotes in GnomAdExome4 at 24 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPN1NM_002950.4 linkuse as main transcriptc.712C>T p.His238Tyr missense_variant 4/10 ENST00000296255.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPN1ENST00000296255.8 linkuse as main transcriptc.712C>T p.His238Tyr missense_variant 4/101 NM_002950.4 P1
RPN1ENST00000497289.5 linkuse as main transcriptc.196C>T p.His66Tyr missense_variant 4/102
RPN1ENST00000495462.5 linkuse as main transcript downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000723
AC:
110
AN:
152174
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0126
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000411
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00211
AC:
531
AN:
251468
Hom.:
9
AF XY:
0.00275
AC XY:
374
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.000217
Gnomad SAS exome
AF:
0.0141
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000624
Gnomad OTH exome
AF:
0.000977
GnomAD4 exome
AF:
0.00115
AC:
1678
AN:
1461878
Hom.:
24
Cov.:
32
AF XY:
0.00156
AC XY:
1131
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.000492
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0130
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000354
Gnomad4 OTH exome
AF:
0.00136
GnomAD4 genome
AF:
0.000729
AC:
111
AN:
152292
Hom.:
1
Cov.:
33
AF XY:
0.000886
AC XY:
66
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000719
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0128
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000412
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000580
Hom.:
1
Bravo
AF:
0.000495
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00207
AC:
251
Asia WGS
AF:
0.00520
AC:
18
AN:
3478

ClinVar

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

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterresearchMolecular Oncology Research Center, Barretos Cancer HospitalAug 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D;T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
MetaRNN
Benign
0.022
T;T
MetaSVM
Uncertain
0.32
D
MutationAssessor
Pathogenic
3.4
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-6.0
D;D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.96
MVP
0.58
MPC
1.1
ClinPred
0.15
T
GERP RS
5.0
Varity_R
0.95
gMVP
0.83

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: rs138936459; hg19: chr3-128350922; API