3-128637893-C-T

Variant names:

• chr3-128637893-C-T
• rs144201770
• NM_002950.4:c.539G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002950.4(RPN1):​c.539G>A​(p.Arg180Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000805 in 1,614,120 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 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: RPN1 NM_002950.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018509746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPN1	NM_002950.4	c.539G>A	p.Arg180Gln	missense_variant	Exon 3 of 10	ENST00000296255.8	NP_002941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPN1	ENST00000296255.8	c.539G>A	p.Arg180Gln	missense_variant	Exon 3 of 10	1	NM_002950.4	ENSP00000296255.3

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251492 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000465 AC: 68 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727242

Gnomad4 AFR exome AF: 0.00128 AC: 43 AN: 33480

Gnomad4 AMR exome AF: 0.0000894 AC: 4 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000135 AC: 15 AN: 1112010

Gnomad4 Remaining exome AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74442

Gnomad4 AFR AF: 0.00137 AC: 0.0013723 AN: 0.0013723

Gnomad4 AMR AF: 0.000131 AC: 0.000130907 AN: 0.000130907

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000441 AC: 0.0000441073 AN: 0.0000441073

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000259 Hom.: 0

Bravo AF: 0.000487

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539G>A (p.R180Q) alteration is located in exon 3 (coding exon 3) of the RPN1 gene. This alteration results from a G to A substitution at nucleotide position 539, causing the arginine (R) at amino acid position 180 to be replaced by a glutamine (Q). 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	Benign	0.18
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.13
Sift	Benign	0.16	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.82	P;.
Vest4		0.38
MVP		0.23
MPC		0.50
ClinPred		0.041	T
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.19
gMVP		0.20
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs144201770; hg19: chr3-128356736;