20-17615937-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001365613.2(RRBP1):c.3940G>A(p.Glu1314Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,610,044 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0034 (19 hom.)
• Consequence: RRBP1 NM_001365613.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.06

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006175071).
• BP6: Variant 20-17615937-C-T is Benign according to our data. Variant chr20-17615937-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 712138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRBP1	NM_001365613.2	c.3940G>A	p.Glu1314Lys	missense_variant	22/25	ENST00000377813.6
RRBP1	NM_001042576.2	c.2641G>A	p.Glu881Lys	missense_variant	23/26
RRBP1	NM_004587.3	c.2641G>A	p.Glu881Lys	missense_variant	22/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRBP1	ENST00000377813.6	c.3940G>A	p.Glu1314Lys	missense_variant	22/25	1	NM_001365613.2	A2

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152230 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00238 AC: 590 AN: 248188 Hom.: 2 AF XY: 0.00243 AC XY: 327 AN XY: 134504

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00925

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.000995

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00335 AC: 4890 AN: 1457696 Hom.: 19 Cov.: 31 AF XY: 0.00342 AC XY: 2480 AN XY: 725344

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00884

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00369

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152348 Hom.: 2 Cov.: 34 AF XY: 0.00232 AC XY: 173 AN XY: 74502

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00314 Hom.: 0

Bravo AF: 0.00251

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00385

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;.;D
MetaRNN	Benign	0.0062	T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D
Polyphen		1.0, 0.99	.;.;D;D;D;D;.
Vest4		0.55
MVP		0.56
MPC		0.29
ClinPred		0.030	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.38

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: rs61737094; hg19: chr20-17596582;