20-17616749-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001365613.2(RRBP1):​c.3850G>C​(p.Glu1284Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. E1284K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06412473).

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>C	p.Glu1284Gln	missense	Exon 21 of 25	NP_001352542.1	Q9P2E9-1
	RRBP1	NM_001042576.2		c.2551G>C	p.Glu851Gln	missense	Exon 22 of 26	NP_001036041.2	Q9P2E9-3
	RRBP1	NM_004587.3		c.2551G>C	p.Glu851Gln	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>C	p.Glu1284Gln	missense	Exon 21 of 25	ENSP00000367044.1	Q9P2E9-1
	RRBP1	ENST00000246043.8	TSL:1	c.3850G>C	p.Glu1284Gln	missense	Exon 19 of 23	ENSP00000246043.4	Q9P2E9-1
	RRBP1	ENST00000360807.8	TSL:1	c.2551G>C	p.Glu851Gln	missense	Exon 21 of 25	ENSP00000354045.4	Q9P2E9-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458224 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725590

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110448

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.6
DANN	Benign	0.82
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.45
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.073
Sift	Benign	0.087	T
Sift4G	Benign	0.095	T
Polyphen		0.036	B
Vest4		0.11
MutPred		0.046		Gain of glycosylation at P1281 (P = 0.2718)
MVP		0.27
MPC		0.10
ClinPred		0.067	T
GERP RS		2.2
Varity_R		0.046
gMVP		0.32
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;