chr20-17619715-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365613.2(RRBP1):​c.3593C>A​(p.Thr1198Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Not reported in ClinVar
• 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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRBP1	NM_001365613.2	c.3593C>A	p.Thr1198Lys	missense_variant	Exon 19 of 25	ENST00000377813.6	NP_001352542.1
RRBP1	NM_001042576.2	c.2294C>A	p.Thr765Lys	missense_variant	Exon 20 of 26		NP_001036041.2
RRBP1	NM_004587.3	c.2294C>A	p.Thr765Lys	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>A	p.Thr1198Lys	missense_variant	Exon 19 of 25	1	NM_001365613.2	ENSP00000367044.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459496 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;.;T;T;.;.;T
Eigen	Benign	0.030
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;L;L;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	.;.;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.55	.;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.99, 0.99	.;.;D;D;D;D;.
Vest4		0.63
MutPred		0.17		.;.;Gain of ubiquitination at T1198 (P = 0.0029);Gain of ubiquitination at T1198 (P = 0.0029);.;.;.;
MVP		0.43
MPC		0.42
ClinPred		0.93	D
GERP RS		3.9
Varity_R		0.053
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs773714203; hg19: chr20-17600360;