20-17615510-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365613.2(RRBP1):c.3971G>C(p.Arg1324Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1324L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14109969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRBP1	NM_001365613.2	c.3971G>C	p.Arg1324Pro	missense_variant	23/25	ENST00000377813.6
RRBP1	NM_001042576.2	c.2672G>C	p.Arg891Pro	missense_variant	24/26
RRBP1	NM_004587.3	c.2672G>C	p.Arg891Pro	missense_variant	23/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRBP1	ENST00000377813.6	c.3971G>C	p.Arg1324Pro	missense_variant	23/25	1	NM_001365613.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Benign	0.96
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.85	D;D;D;.;D;.;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.070	T;T;T;T;T;T;T
Polyphen		0.34, 0.85	.;.;B;B;P;P;.
Vest4		0.34
MutPred		0.14		.;.;Gain of glycosylation at R1324 (P = 0.0785);Gain of glycosylation at R1324 (P = 0.0785);.;.;.;
MVP		0.32
MPC		0.42
ClinPred		0.36	T
GERP RS		-0.63
Varity_R		0.41
gMVP		0.23

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: rs1132274; hg19: chr20-17596155;