20-17616724-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001365613.2(RRBP1):c.3867+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,594,136 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (123 hom., cov: 34)
  • Exomes 𝑓: 0.0023 (108 hom.)
• Consequence: RRBP1 NM_001365613.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003269
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0840

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 (BayesDel_noAF=-0.69).
• BP6: Variant 20-17616724-G-A is Benign according to our data. Variant chr20-17616724-G-A is described in ClinVar as [Benign]. Clinvar id is 781544.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRBP1	NM_001365613.2	c.3867+8C>T		splice_region_variant, intron_variant		ENST00000377813.6
RRBP1	NM_001042576.2	c.2568+8C>T		splice_region_variant, intron_variant
RRBP1	NM_004587.3	c.2568+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRBP1	ENST00000377813.6	c.3867+8C>T		splice_region_variant, intron_variant		1	NM_001365613.2	A2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3366 AN: 152192 Hom.: 123 Cov.: 34

Gnomad AFR AF: 0.0770

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00599 AC: 1458 AN: 243554 Hom.: 50 AF XY: 0.00438 AC XY: 579 AN XY: 132180

Gnomad AFR exome AF: 0.0803

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00229 AC: 3304 AN: 1441826 Hom.: 108 Cov.: 30 AF XY: 0.00191 AC XY: 1372 AN XY: 718388

Gnomad4 AFR exome AF: 0.0781

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000199

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000205

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.0221 AC: 3371 AN: 152310 Hom.: 123 Cov.: 34 AF XY: 0.0204 AC XY: 1519 AN XY: 74454

Gnomad4 AFR AF: 0.0769

Gnomad4 AMR AF: 0.00751

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0101 Hom.: 17

Bravo AF: 0.0250

Asia WGS AF: 0.00433 AC: 16 AN: 3478

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

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	3.7
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs56102376; hg19: chr20-17597369;