chr20-17616749-C-T

Variant names:

• chr20-17616749-C-T
• rs200224134
• NM_001365613.2:c.3850G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 16/22 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
• Publications: 4 publications found

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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008036047).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365613.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRBP1	NM_001365613.2	MANE Select	c.3850G>A	p.Glu1284Lys	missense	Exon 21 of 25	NP_001352542.1	Q9P2E9-1
	RRBP1	NM_001042576.2		c.2551G>A	p.Glu851Lys	missense	Exon 22 of 26	NP_001036041.2	Q9P2E9-3
	RRBP1	NM_004587.3		c.2551G>A	p.Glu851Lys	missense	Exon 21 of 25	NP_004578.3	Q9P2E9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRBP1	ENST00000377813.6	TSL:1 MANE Select	c.3850G>A	p.Glu1284Lys	missense	Exon 21 of 25	ENSP00000367044.1	Q9P2E9-1
	RRBP1	ENST00000246043.8	TSL:1	c.3850G>A	p.Glu1284Lys	missense	Exon 19 of 23	ENSP00000246043.4	Q9P2E9-1
	RRBP1	ENST00000360807.8	TSL:1	c.2551G>A	p.Glu851Lys	missense	Exon 21 of 25	ENSP00000354045.4	Q9P2E9-3

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

GnomAD2 exomes AF: 0.000469 AC: 116 AN: 247380 AF XY: 0.000500

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 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

African (AFR) AF: 0.0000300 AC: 1 AN: 33302

American (AMR) AF: 0.0000452 AC: 2 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 75 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.000407 AC: 35 AN: 86048

European-Finnish (FIN) AF: 0.0000380 AC: 2 AN: 52598

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.000736 AC: 817 AN: 1110438

Other (OTH) AF: 0.000581 AC: 35 AN: 60244

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

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.45
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.043
Sift	Benign	0.13	T
Sift4G	Benign	0.086	T
Polyphen		0.034	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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs200224134; hg19: chr20-17597394; COSMIC: COSV55698134;