20-17624595-A-G

Variant names:

• chr20-17624595-A-G
• rs6034867
• NM_001365613.2:c.3128T>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.3128T>C​(p.Leu1043Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270
• Publications: 29 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=0.02863127).

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.3128T>C	p.Leu1043Pro	missense	Exon 13 of 25	NP_001352542.1
	RRBP1	NM_001042576.2		c.1829T>C	p.Leu610Pro	missense	Exon 14 of 26	NP_001036041.2
	RRBP1	NM_004587.3		c.1829T>C	p.Leu610Pro	missense	Exon 13 of 25	NP_004578.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRBP1	ENST00000377813.6	TSL:1 MANE Select	c.3128T>C	p.Leu1043Pro	missense	Exon 13 of 25	ENSP00000367044.1
	RRBP1	ENST00000246043.8	TSL:1	c.3128T>C	p.Leu1043Pro	missense	Exon 11 of 23	ENSP00000246043.4
	RRBP1	ENST00000360807.8	TSL:1	c.1829T>C	p.Leu610Pro	missense	Exon 13 of 25	ENSP00000354045.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1440362 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 714140

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 41318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.00 AC: 0 AN: 39004

South Asian (SAS) AF: 0.00 AC: 0 AN: 82280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101792

Other (OTH) AF: 0.00 AC: 0 AN: 59662

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 7749

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.27
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.025
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		0.098	B
Vest4		0.25
MutPred		0.15		Loss of stability (P = 0.0518)
MVP		0.17
MPC		0.17
ClinPred		0.13	T
GERP RS		1.6
Varity_R		0.13
gMVP		0.43
Mutation Taster		=89/11	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: rs6034867; hg19: chr20-17605240;