Genetic Variant NM_001365613.2:c.3940G>T (chr20-17615937-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001365613.2(RRBP1):c.3940G>T(p.Glu1314*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RRBP1
NM_001365613.2 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

Publications

0 publications found

Variant links:

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]

RRBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRBP1	NM_001365613.2	MANE Select	c.3940G>T	p.Glu1314*	stop_gained	Exon 22 of 25	NP_001352542.1	Q9P2E9-1
RRBP1	NM_001042576.2		c.2641G>T	p.Glu881*	stop_gained	Exon 23 of 26	NP_001036041.2	Q9P2E9-3
RRBP1	NM_004587.3		c.2641G>T	p.Glu881*	stop_gained	Exon 22 of 25	NP_004578.3	Q9P2E9-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRBP1	ENST00000377813.6	TSL:1 MANE Select	c.3940G>T	p.Glu1314*	stop_gained	Exon 22 of 25	ENSP00000367044.1	Q9P2E9-1
RRBP1	ENST00000246043.8	TSL:1	c.3940G>T	p.Glu1314*	stop_gained	Exon 20 of 23	ENSP00000246043.4	Q9P2E9-1
RRBP1	ENST00000360807.8	TSL:1	c.2641G>T	p.Glu881*	stop_gained	Exon 22 of 25	ENSP00000354045.4	Q9P2E9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111882

Other (OTH)

AF:

0.00

AC:

AN:

60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

PhyloP100

2.1

Vest4

0.28

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=15/185

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over