dbSNP rs150096055: RPN1:c.633+6C>T (chr3-128637793-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002950.4(RPN1):c.633+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0095 in 1,609,678 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 90 hom. )

Consequence

RPN1
NM_002950.4 splice_region, intron

Scores

Splicing: ADA: 0.00002130

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.269

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 3-128637793-G-A is Benign according to our data. Variant chr3-128637793-G-A is described in ClinVar as Benign. ClinVar VariationId is 774848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 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.633+6C>T		splice_region intron	N/A	NP_002941.1	P04843

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPN1	ENST00000296255.8	TSL:1 MANE Select	c.633+6C>T	splice_region intron	N/A	ENSP00000296255.3	P04843
RPN1	ENST00000874295.1		c.633+6C>T	splice_region intron	N/A	ENSP00000544354.1
RPN1	ENST00000916581.1		c.633+6C>T	splice_region intron	N/A	ENSP00000586640.1

Frequencies

GnomAD3 genomes

AF:

0.00681

AC:

1036

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00766

AC:

1918

AN:

250436

AF XY:

0.00771

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00324

Gnomad ASJ exome

AF:

0.00230

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00818

GnomAD4 exome

AF:

0.00979

AC:

14262

AN:

1457388

Hom.:

Cov.:

AF XY:

0.00959

AC XY:

6949

AN XY:

724472

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

33382

American (AMR)

AF:

0.00327

AC:

146

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00219

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00473

AC:

407

AN:

86116

European-Finnish (FIN)

AF:

0.0147

AC:

786

AN:

53324

Middle Eastern (MID)

AF:

0.00467

AC:

AN:

4282

European-Non Finnish (NFE)

AF:

0.0111

AC:

12336

AN:

1109768

Other (OTH)

AF:

0.00760

AC:

457

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

657

1314

1972

2629

3286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.00680

AC:

1036

AN:

152290

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

520

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41564

American (AMR)

AF:

0.00255

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00373

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0168

AC:

178

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0100

AC:

683

AN:

68034

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00748

Hom.:

Bravo

AF:

0.00577

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00954

EpiControl

AF:

0.00984

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.0

(source)

DANN

Benign

0.49

PhyloP100

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0020

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

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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