20-17614825-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001365613.2(RRBP1):c.4106G>A(p.Arg1369Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,906 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0086 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (18 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.46

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034346282).
• BP6: Variant 20-17614825-C-T is Benign according to our data. Variant chr20-17614825-C-T is described in ClinVar as [Benign]. Clinvar id is 710867.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00863 (1315/152352) while in subpopulation AFR AF= 0.0296 (1229/41584). AF 95% confidence interval is 0.0282. There are 18 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRBP1	NM_001365613.2	c.4106G>A	p.Arg1369Lys	missense_variant	24/25	ENST00000377813.6
RRBP1	NM_001042576.2	c.2807G>A	p.Arg936Lys	missense_variant	25/26
RRBP1	NM_004587.3	c.2807G>A	p.Arg936Lys	missense_variant	24/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRBP1	ENST00000377813.6	c.4106G>A	p.Arg1369Lys	missense_variant	24/25	1	NM_001365613.2	A2

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1313 AN: 152234 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00233 AC: 586 AN: 251250 Hom.: 8 AF XY: 0.00176 AC XY: 239 AN XY: 135812

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000922 AC: 1348 AN: 1461554 Hom.: 18 Cov.: 34 AF XY: 0.000791 AC XY: 575 AN XY: 727092

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00863 AC: 1315 AN: 152352 Hom.: 18 Cov.: 33 AF XY: 0.00819 AC XY: 610 AN XY: 74500

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00149 Hom.: 10

Bravo AF: 0.00974

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	13
Dann	Benign	0.75
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.46	T;T;T;.;T;.;T
MetaRNN	Benign	0.0034	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;B;B;.
Vest4		0.11
MVP		0.26
MPC		0.10
ClinPred		0.0023	T
GERP RS		4.3
Varity_R		0.038
gMVP		0.051

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2229887; hg19: chr20-17595470;