Genetic Variant RRBP1:p.Arg1369Lys (chr20-17614825-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365613.2(RRBP1):c.4106G>A(p.Arg1369Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,906 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 18 hom., cov: 33)

Exomes 𝑓: 0.00092 ( 18 hom. )

Consequence

RRBP1
NM_001365613.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.46

Publications

8 publications found

Variant links:

Genes affected

RRBP1 (HGNC:10448): (ribosome binding protein 1) This gene encodes a ribosome-binding protein of the endoplasmic reticulum (ER) membrane. Studies suggest that this gene plays a role in ER proliferation, secretory pathways and secretory cell differentiation, and mediation of ER-microtubule interactions. Alternative splicing has been observed and protein isoforms are characterized by regions of N-terminal decapeptide and C-terminal heptad repeats. Splicing of the tandem repeats results in variations in ribosome-binding affinity and secretory function. The full-length nature of variants which differ in repeat length has not been determined. Pseudogenes of this gene have been identified on chromosomes 3 and 7, and RRBP1 has been excluded as a candidate gene in the cause of Alagille syndrome, the result of a mutation in a nearby gene on chromosome 20p12. [provided by RefSeq, Apr 2012]

RRBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034346282).

BP6

Variant 20-17614825-C-T is Benign according to our data. Variant chr20-17614825-C-T is described in ClinVar as Benign. ClinVar VariationId is 710867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00863 (1315/152352) while in subpopulation AFR AF = 0.0296 (1229/41584). AF 95% confidence interval is 0.0282. There are 18 homozygotes in GnomAd4. There are 610 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365613.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRBP1	NM_001365613.2	MANE Select	c.4106G>A	p.Arg1369Lys	missense	Exon 24 of 25	NP_001352542.1	Q9P2E9-1
RRBP1	NM_001042576.2		c.2807G>A	p.Arg936Lys	missense	Exon 25 of 26	NP_001036041.2	Q9P2E9-3
RRBP1	NM_004587.3		c.2807G>A	p.Arg936Lys	missense	Exon 24 of 25	NP_004578.3	Q9P2E9-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRBP1	ENST00000377813.6	TSL:1 MANE Select	c.4106G>A	p.Arg1369Lys	missense	Exon 24 of 25	ENSP00000367044.1	Q9P2E9-1
RRBP1	ENST00000246043.8	TSL:1	c.4106G>A	p.Arg1369Lys	missense	Exon 22 of 23	ENSP00000246043.4	Q9P2E9-1
RRBP1	ENST00000360807.8	TSL:1	c.2807G>A	p.Arg936Lys	missense	Exon 24 of 25	ENSP00000354045.4	Q9P2E9-3

Frequencies

GnomAD3 genomes

AF:

0.00862

AC:

1313

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00233

AC:

586

AN:

251250

AF XY:

0.00176

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000922

AC:

1348

AN:

1461554

Hom.:

Cov.:

AF XY:

0.000791

AC XY:

575

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.0299

AC:

1001

AN:

33480

American (AMR)

AF:

0.00199

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000791

AC:

AN:

1111990

Other (OTH)

AF:

0.00238

AC:

144

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00863

AC:

1315

AN:

152352

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

610

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0296

AC:

1229

AN:

41584

American (AMR)

AF:

0.00399

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

138

207

276

345

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:

0.00328

Hom.:

Bravo

AF:

0.00974

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0259

AC:

114

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00285

AC:

346

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

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

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.037

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.1

PhyloP100

3.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

1.4

REVEL

Benign

0.055

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MVP

0.26

MPC

0.10

ClinPred

0.0023

GERP RS

4.3

Varity_R

0.038

gMVP

0.051

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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