20-17616749-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001365613.2(RRBP1):c.3850G>A(p.Glu1284Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000625 in 1,610,526 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00066 (3 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.447

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008036047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRBP1	NM_001365613.2	c.3850G>A	p.Glu1284Lys	missense_variant	21/25	ENST00000377813.6
RRBP1	NM_001042576.2	c.2551G>A	p.Glu851Lys	missense_variant	22/26
RRBP1	NM_004587.3	c.2551G>A	p.Glu851Lys	missense_variant	21/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRBP1	ENST00000377813.6	c.3850G>A	p.Glu1284Lys	missense_variant	21/25	1	NM_001365613.2	A2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152194 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000469 AC: 116 AN: 247380 Hom.: 0 AF XY: 0.000500 AC XY: 67 AN XY: 133878

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00332

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000494

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000527

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000665 AC: 969 AN: 1458214 Hom.: 3 Cov.: 32 AF XY: 0.000685 AC XY: 497 AN XY: 725584

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00288

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000407

Gnomad4 FIN exome AF: 0.0000380

Gnomad4 NFE exome AF: 0.000736

Gnomad4 OTH exome AF: 0.000581

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152312 Hom.: 0 Cov.: 34 AF XY: 0.000295 AC XY: 22 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000763 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000428 AC: 52

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.2551G>A (p.E851K) alteration is located in exon 22 (coding exon 20) of the RRBP1 gene. This alteration results from a G to A substitution at nucleotide position 2551, causing the glutamic acid (E) at amino acid position 851 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	0.060
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	7.2
Dann	Benign	0.85
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.70	T;T;T;.;T;.;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0080	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.086	T;T;D;D;T;T;T
Polyphen		0.034, 0.0070	.;.;B;B;B;B;.
Vest4		0.11
MVP		0.26
MPC		0.12
ClinPred		0.019	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.029
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200224134; hg19: chr20-17597394; COSMIC: COSV55698134;