3-128620541-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002950.4(RPN1):c.1694C>T(p.Ser565Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,994 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )
Consequence
RPN1
NM_002950.4 missense
NM_002950.4 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 7.38
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=0.11975658).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPN1 | NM_002950.4 | c.1694C>T | p.Ser565Leu | missense_variant | 10/10 | ENST00000296255.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPN1 | ENST00000296255.8 | c.1694C>T | p.Ser565Leu | missense_variant | 10/10 | 1 | NM_002950.4 | P1 | |
RPN1 | ENST00000497289.5 | c.1178C>T | p.Ser393Leu | missense_variant | 10/10 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249112Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134868
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GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461782Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 727192
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74364
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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 submitter | clinical testing | Ambry Genetics | Feb 22, 2023 | The c.1694C>T (p.S565L) alteration is located in exon 10 (coding exon 10) of the RPN1 gene. This alteration results from a C to T substitution at nucleotide position 1694, causing the serine (S) at amino acid position 565 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Loss of disorder (P = 0.043);.;
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at