Genetic Variant RRBP1:p.Leu1043His (chr20-17624595-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001365613.2(RRBP1):c.3128T>A(p.Leu1043His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,592,674 control chromosomes in the GnomAD database, including 796,245 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 1.0 ( 76105 hom., cov: 33)

Exomes 𝑓: 1.0 ( 720140 hom. )

Consequence

RRBP1
NM_001365613.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.270

Publications

29 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.4000606E-7).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RRBP1	NM_001365613.2 link	c.3128T>A	p.Leu1043His	missense_variant	Exon 13 of 25	ENST00000377813.6	NP_001352542.1
RRBP1	NM_001042576.2 link	c.1829T>A	p.Leu610His	missense_variant	Exon 14 of 26		NP_001036041.2
RRBP1	NM_004587.3 link	c.1829T>A	p.Leu610His	missense_variant	Exon 13 of 25		NP_004578.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRBP1	ENST00000377813.6 link	c.3128T>A	p.Leu1043His	missense_variant	Exon 13 of 25	1	NM_001365613.2	ENSP00000367044.1

Frequencies

GnomAD3 genomes

AF:

1.00

AC:

152143

AN:

152194

Hom.:

76046

Cov.:

show subpopulations

Gnomad AFR

AF:

0.999

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

1.00

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

1.00

GnomAD2 exomes

AF:

1.00

AC:

217443

AN:

217454

AF XY:

1.00

show subpopulations

Gnomad AFR exome

AF:

0.999

Gnomad AMR exome

AF:

1.00

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

1.00

GnomAD4 exome

AF:

1.00

AC:

1440321

AN:

1440362

Hom.:

720140

Cov.:

AF XY:

1.00

AC XY:

714124

AN XY:

714140

show subpopulations

African (AFR)

AF:

0.999

AC:

33305

AN:

33342

American (AMR)

AF:

1.00

AC:

41318

AN:

41318

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

25564

AN:

25564

East Asian (EAS)

AF:

1.00

AC:

39004

AN:

39004

South Asian (SAS)

AF:

1.00

AC:

82280

AN:

82280

European-Finnish (FIN)

AF:

1.00

AC:

51668

AN:

51668

Middle Eastern (MID)

AF:

1.00

AC:

5732

AN:

5732

European-Non Finnish (NFE)

AF:

1.00

AC:

1101792

AN:

1101792

Other (OTH)

AF:

1.00

AC:

59658

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21560

43120

64680

86240

107800

<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:

1.00

AC:

152261

AN:

152312

Hom.:

76105

Cov.:

AF XY:

1.00

AC XY:

74447

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.999

AC:

41521

AN:

41572

American (AMR)

AF:

1.00

AC:

15306

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5158

AN:

5158

South Asian (SAS)

AF:

1.00

AC:

4832

AN:

4832

European-Finnish (FIN)

AF:

1.00

AC:

10626

AN:

10626

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68028

AN:

68028

Other (OTH)

AF:

1.00

AC:

2112

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.995

Hom.:

7749

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

1.00

AC:

4403

ESP6500EA

AF:

1.00

AC:

8600

ExAC

AF:

1.00

AC:

120004

Asia WGS

AF:

1.00

AC:

3478

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.0

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.0

.;T;T;.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.0091

T;T;.;T;.;T

MetaRNN

Benign

5.4e-7

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N;.;.;.

PhyloP100

0.27

PrimateAI

Benign

0.24

PROVEAN

Benign

0.0

.;N;N;N;N;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T;T

Vest4

0.093

ClinPred

0.00063

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.094

Mutation Taster

=98/2

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over