rs11960

Positions:

• chr20-17619712-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000377813.6(RRBP1):​c.3596C>T​(p.Ser1199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 1,610,528 control chromosomes in the GnomAD database, including 383,119 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.54 (27381 hom., cov: 33)
  • Exomes 𝑓: 0.69 (355738 hom.)
• Consequence: RRBP1 ENST00000377813.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6560502E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRBP1	NM_001365613.2	c.3596C>T	p.Ser1199Leu	missense_variant	19/25	ENST00000377813.6	NP_001352542.1
RRBP1	NM_001042576.2	c.2297C>T	p.Ser766Leu	missense_variant	20/26		NP_001036041.2
RRBP1	NM_004587.3	c.2297C>T	p.Ser766Leu	missense_variant	19/25		NP_004578.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRBP1	ENST00000377813.6	c.3596C>T	p.Ser1199Leu	missense_variant	19/25	1	NM_001365613.2	ENSP00000367044	A2

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81928 AN: 152052 Hom.: 27389 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.729

Gnomad OTH AF: 0.603

GnomAD3 exomes AF: 0.621 AC: 154745 AN: 249008 Hom.: 52411 AF XY: 0.630 AC XY: 85031 AN XY: 134870

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.549

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.685

GnomAD4 exome AF: 0.687 AC: 1002381 AN: 1458356 Hom.: 355738 Cov.: 38 AF XY: 0.685 AC XY: 497256 AN XY: 725470

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.617

Gnomad4 ASJ exome AF: 0.769

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.554

Gnomad4 FIN exome AF: 0.761

Gnomad4 NFE exome AF: 0.727

Gnomad4 OTH exome AF: 0.663

GnomAD4 genome AF: 0.538 AC: 81920 AN: 152172 Hom.: 27381 Cov.: 33 AF XY: 0.539 AC XY: 40125 AN XY: 74410

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.772

Gnomad4 NFE AF: 0.729

Gnomad4 OTH AF: 0.600

Alfa AF: 0.673 Hom.: 52649

Bravo AF: 0.508

TwinsUK AF: 0.716 AC: 2654

ALSPAC AF: 0.732 AC: 2821

ESP6500AA AF: 0.155 AC: 684

ESP6500EA AF: 0.725 AC: 6235

ExAC AF: 0.611 AC: 74115

Asia WGS AF: 0.473 AC: 1651 AN: 3478

EpiCase AF: 0.728

EpiControl AF: 0.732

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.38	.;.;T;T;.;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	T;T;T;.;T;.;T
MetaRNN	Benign	0.0000017	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	.;.;L;L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	.;.;N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.23	.;.;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;T
Polyphen		0.086, 0.062	.;.;B;B;B;B;.
Vest4		0.17
MPC		0.26
ClinPred		0.0077	T
GERP RS		2.9
Varity_R		0.059
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11960; hg19: chr20-17600357; COSMIC: COSV55700059;