dbSNP rs1042514038: RRBP1:p.Leu1363Arg (chr20-17614843-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001365613.2(RRBP1):c.4088T>G(p.Leu1363Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1363P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

RRBP1
NM_001365613.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.49

Publications

0 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:

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ACMG classification

Classification was made for transcript

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

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.4088T>G	p.Leu1363Arg	missense	Exon 24 of 25	NP_001352542.1	Q9P2E9-1
RRBP1	NM_001042576.2		c.2789T>G	p.Leu930Arg	missense	Exon 25 of 26	NP_001036041.2	Q9P2E9-3
RRBP1	NM_004587.3		c.2789T>G	p.Leu930Arg	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.4088T>G	p.Leu1363Arg	missense	Exon 24 of 25	ENSP00000367044.1	Q9P2E9-1
RRBP1	ENST00000246043.8	TSL:1	c.4088T>G	p.Leu1363Arg	missense	Exon 22 of 23	ENSP00000246043.4	Q9P2E9-1
RRBP1	ENST00000360807.8	TSL:1	c.2789T>G	p.Leu930Arg	missense	Exon 24 of 25	ENSP00000354045.4	Q9P2E9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.9

PhyloP100

6.5

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Benign

0.26

Polyphen

1.0

Vest4

0.90

MutPred

0.25

Gain of methylation at L1363 (P = 0.0118)

MVP

0.65

MPC

0.56

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.62

Mutation Taster

=44/56

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over