20-17619715-G-A

Variant names:

• chr20-17619715-G-A
• rs773714203
• NM_001365613.2:c.3593C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001365613.2(RRBP1):​c.3593C>T​(p.Thr1198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,611,722 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000024 (1 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2153312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRBP1	NM_001365613.2	c.3593C>T	p.Thr1198Met	missense_variant	Exon 19 of 25	ENST00000377813.6	NP_001352542.1
RRBP1	NM_001042576.2	c.2294C>T	p.Thr765Met	missense_variant	Exon 20 of 26		NP_001036041.2
RRBP1	NM_004587.3	c.2294C>T	p.Thr765Met	missense_variant	Exon 19 of 25		NP_004578.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRBP1	ENST00000377813.6	c.3593C>T	p.Thr1198Met	missense_variant	Exon 19 of 25	1	NM_001365613.2	ENSP00000367044.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000361 AC: 9 AN: 249030 AF XY: 0.0000593

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1459496 Hom.: 1 Cov.: 31 AF XY: 0.0000317 AC XY: 23 AN XY: 726026

Gnomad4 AFR exome AF: 0.000149 AC: 5 AN: 33454

Gnomad4 AMR exome AF: 0.0000449 AC: 2 AN: 44566

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26026

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39668

Gnomad4 SAS exome AF: 0.000163 AC: 14 AN: 86050

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52570

Gnomad4 NFE exome AF: 0.00000990 AC: 11 AN: 1111078

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60322

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152226 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.0000965 AC: 0.0000964646 AN: 0.0000964646

Gnomad4 AMR AF: 0.000392 AC: 0.000392465 AN: 0.000392465

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2294C>T (p.T765M) alteration is located in exon 20 (coding exon 18) of the RRBP1 gene. This alteration results from a C to T substitution at nucleotide position 2294, causing the threonine (T) at amino acid position 765 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;T;T;.;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;L;L;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	.;.;N;N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.10	.;.;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T
Polyphen		1.0, 0.96	.;.;D;D;D;D;.
Vest4		0.34
MVP		0.45
MPC		0.47
ClinPred		0.45	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.19
Mutation Taster		=92/8	polymorphism

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: rs773714203; hg19: chr20-17600360; COSMIC: COSV55698981;