Genetic Variant NM_002950.4:c.712C>T (chr3-128632079-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -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

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.42

Publications

8 publications found

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]

RPN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002950.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPN1	NM_002950.4	MANE Select	c.712C>T	p.His238Tyr	missense	Exon 4 of 10	NP_002941.1	P04843

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPN1	ENST00000296255.8	TSL:1 MANE Select	c.712C>T	p.His238Tyr	missense	Exon 4 of 10	ENSP00000296255.3	P04843
RPN1	ENST00000874295.1		c.712C>T	p.His238Tyr	missense	Exon 4 of 10	ENSP00000544354.1
RPN1	ENST00000916581.1		c.712C>T	p.His238Tyr	missense	Exon 4 of 10	ENSP00000586640.1

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152174

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00211

AC:

531

AN:

251468

AF XY:

0.00275

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 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.:

Cov.:

AF XY:

0.00156

AC XY:

1131

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000492

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0130

AC:

1123

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000354

AC:

394

AN:

1112006

Other (OTH)

AF:

0.00136

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

102

204

305

407

509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152292

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41552

American (AMR)

AF:

0.000719

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0128

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000700

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00207

AC:

251

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary breast ovarian cancer syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.022

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

3.4

PhyloP100

9.4

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.58

MPC

1.1

ClinPred

0.15

GERP RS

5.0

Varity_R

0.95

gMVP

0.83

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over