20-17619665-C-T

Variant names:

• chr20-17619665-C-T
• rs550347689
• NM_001365613.2:c.3643G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001365613.2(RRBP1):​c.3643G>A​(p.Glu1215Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000049 in 1,612,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRBP1	NM_001365613.2	c.3643G>A	p.Glu1215Lys	missense_variant	Exon 19 of 25	ENST00000377813.6	NP_001352542.1
RRBP1	NM_001042576.2	c.2344G>A	p.Glu782Lys	missense_variant	Exon 20 of 26		NP_001036041.2
RRBP1	NM_004587.3	c.2344G>A	p.Glu782Lys	missense_variant	Exon 19 of 25		NP_004578.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRBP1	ENST00000377813.6	c.3643G>A	p.Glu1215Lys	missense_variant	Exon 19 of 25	1	NM_001365613.2	ENSP00000367044.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249498 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1460370 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 726488

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33468

Gnomad4 AMR exome AF: 0.0000448 AC: 2 AN: 44628

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26074

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39672

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86150

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52564

Gnomad4 NFE exome AF: 0.0000603 AC: 67 AN: 1111704

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.0000483 AC: 0.0000482672 AN: 0.0000482672

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000735 AC: 0.0000734883 AN: 0.0000734883

Gnomad4 OTH AF: 0.000478 AC: 0.000478011 AN: 0.000478011

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2344G>A (p.E782K) alteration is located in exon 20 (coding exon 18) of the RRBP1 gene. This alteration results from a G to A substitution at nucleotide position 2344, causing the glutamic acid (E) at amino acid position 782 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	.;.;T;T;.;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;.;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.0	.;.;M;M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	.;.;D;D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	.;.;D;D;D;D;D
Sift4G	Uncertain	0.016	D;T;T;T;T;T;T
Polyphen		1.0	.;.;D;D;D;D;.
Vest4		0.60
MVP		0.64
MPC		0.29
ClinPred		0.81	D
GERP RS		5.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.098
gMVP		0.29
Mutation Taster		=77/23	polymorphism

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

LitVar

Other links and lift over

dbSNP: rs550347689; hg19: chr20-17600310;