3-128625978-G-A

Variant names:

• chr3-128625978-G-A
• rs149030563
• NM_002950.4:c.1171C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002950.4(RPN1):​c.1171C>T​(p.Arg391Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,611,416 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 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RPN1 NM_002950.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29

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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPN1	NM_002950.4	c.1171C>T	p.Arg391Cys	missense_variant	Exon 7 of 10	ENST00000296255.8	NP_002941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPN1	ENST00000296255.8	c.1171C>T	p.Arg391Cys	missense_variant	Exon 7 of 10	1	NM_002950.4	ENSP00000296255.3
RPN1	ENST00000497289.5	c.655C>T	p.Arg219Cys	missense_variant	Exon 7 of 10	2		ENSP00000417529.1
RPN1	ENST00000490166.1	n.569C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000480

GnomAD2 exomes AF: 0.0000363 AC: 9 AN: 247606 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000598

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1459328 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725950

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33326

Gnomad4 AMR exome AF: 0.0000684 AC: 3 AN: 43878

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26010

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39678

Gnomad4 SAS exome AF: 0.0000816 AC: 7 AN: 85806

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53402

Gnomad4 NFE exome AF: 0.0000126 AC: 14 AN: 1111184

Gnomad4 Remaining exome AF: 0.0000498 AC: 3 AN: 60296

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241488 AN: 0.0000241488

Gnomad4 AMR AF: 0.0000655 AC: 0.000065548 AN: 0.000065548

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000192 AC: 0.000192456 AN: 0.000192456

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000480 AC: 0.000479846 AN: 0.000479846

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1171C>T (p.R391C) alteration is located in exon 7 (coding exon 7) of the RPN1 gene. This alteration results from a C to T substitution at nucleotide position 1171, causing the arginine (R) at amino acid position 391 to be replaced by a cysteine (C). 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.84
MVP		0.54
MPC		0.94
ClinPred		0.89	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.75
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149030563; hg19: chr3-128344821;