20-17615528-G-T

Variant names:

• chr20-17615528-G-T
• NM_001365613.2:c.3953C>A

Variant summary

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

The NM_001365613.2(RRBP1):​c.3953C>A​(p.Ala1318Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,222 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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, splice_region
• Scores: Splicing: ADA: 0.03333
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.53

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.3953C>A	p.Ala1318Asp	missense_variant, splice_region_variant	Exon 23 of 25	ENST00000377813.6	NP_001352542.1
RRBP1	NM_001042576.2	c.2654C>A	p.Ala885Asp	missense_variant, splice_region_variant	Exon 24 of 26		NP_001036041.2
RRBP1	NM_004587.3	c.2654C>A	p.Ala885Asp	missense_variant, splice_region_variant	Exon 23 of 25		NP_004578.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRBP1	ENST00000377813.6	c.3953C>A	p.Ala1318Asp	missense_variant, splice_region_variant	Exon 23 of 25	1	NM_001365613.2	ENSP00000367044.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451222 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721824

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: 0.0000189

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	.;.;D;D;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;.;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	.;.;M;M;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	.;.;D;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	.;.;D;D;D;D;D
Sift4G	Benign	0.061	T;T;T;T;T;T;T
Polyphen		1.0, 0.93	.;.;D;D;P;P;.
Vest4		0.63
MutPred		0.075		.;.;Gain of phosphorylation at T1320 (P = 0.1208);Gain of phosphorylation at T1320 (P = 0.1208);.;.;.;
MVP		0.54
MPC		0.53
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.20
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.033
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-17596173;