rs199738294

Variant names:

• chr20-17619668-C-T
• rs199738294
• NM_001365613.2:c.3640G>A

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.3640G>A​(p.Ala1214Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,460,426 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.900
• 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=0.06257135).

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.3640G>A	p.Ala1214Thr	missense	Exon 19 of 25	NP_001352542.1	Q9P2E9-1
	RRBP1	NM_001042576.2		c.2341G>A	p.Ala781Thr	missense	Exon 20 of 26	NP_001036041.2	Q9P2E9-3
	RRBP1	NM_004587.3		c.2341G>A	p.Ala781Thr	missense	Exon 19 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.3640G>A	p.Ala1214Thr	missense	Exon 19 of 25	ENSP00000367044.1	Q9P2E9-1
	RRBP1	ENST00000246043.8	TSL:1	c.3640G>A	p.Ala1214Thr	missense	Exon 17 of 23	ENSP00000246043.4	Q9P2E9-1
	RRBP1	ENST00000360807.8	TSL:1	c.2341G>A	p.Ala781Thr	missense	Exon 19 of 25	ENSP00000354045.4	Q9P2E9-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000521 AC: 13 AN: 249454 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460426 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 726528

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111732

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000516 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.067
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		0.90
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.034
Sift	Benign	0.35	T
Sift4G	Benign	0.34	T
Polyphen		0.35	B
Vest4		0.12
MVP		0.38
MPC		0.35
ClinPred		0.070	T
GERP RS		2.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.013
gMVP		0.036
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs199738294; hg19: chr20-17600313; COSMIC: COSV55698013;