chr20-17615510-C-A

Position:

• chr20-17615510-C-A

Variant summary

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

The NM_001365613.2(RRBP1):​c.3971G>T​(p.Arg1324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,604,116 control chromosomes in the GnomAD database, including 27,655 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2199 hom., cov: 33)
  • Exomes 𝑓: 0.17 (25456 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.352033E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRBP1	NM_001365613.2	c.3971G>T	p.Arg1324Leu	missense_variant	23/25	ENST00000377813.6	NP_001352542.1
RRBP1	NM_001042576.2	c.2672G>T	p.Arg891Leu	missense_variant	24/26		NP_001036041.2
RRBP1	NM_004587.3	c.2672G>T	p.Arg891Leu	missense_variant	23/25		NP_004578.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRBP1	ENST00000377813.6	c.3971G>T	p.Arg1324Leu	missense_variant	23/25	1	NM_001365613.2	ENSP00000367044	A2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21949 AN: 152110 Hom.: 2191 Cov.: 33

Gnomad AFR AF: 0.0630

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.194 AC: 46546 AN: 240544 Hom.: 5888 AF XY: 0.198 AC XY: 25830 AN XY: 130592

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.495

Gnomad SAS exome AF: 0.317

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.170 AC: 246861 AN: 1451888 Hom.: 25456 Cov.: 32 AF XY: 0.174 AC XY: 125733 AN XY: 722196

Gnomad4 AFR exome AF: 0.0581

Gnomad4 AMR exome AF: 0.208

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.515

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.144 AC: 21978 AN: 152228 Hom.: 2199 Cov.: 33 AF XY: 0.150 AC XY: 11126 AN XY: 74420

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.501

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.134

Alfa AF: 0.153 Hom.: 3115

Bravo AF: 0.142

TwinsUK AF: 0.166 AC: 614

ALSPAC AF: 0.147 AC: 568

ESP6500AA AF: 0.0679 AC: 299

ESP6500EA AF: 0.151 AC: 1302

ExAC AF: 0.200 AC: 24259

Asia WGS AF: 0.303 AC: 1052 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.041	.;.;T;T;.;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.58	T;T;T;.;T;.;T
MetaRNN	Benign	0.00044	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.88	.;.;L;L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	.;.;N;N;N;N;N
REVEL	Benign	0.012
Sift	Benign	0.32	.;.;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T
Polyphen		0.093, 0.53	.;.;B;B;P;P;.
Vest4		0.29
MPC		0.28
ClinPred		0.0031	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.084

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: rs1132274; hg19: chr20-17596155; COSMIC: COSV55708041;