12-68650446-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001010942.3(RAP1B):​c.104C>T​(p.Thr35Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RAP1B
NM_001010942.3 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.85
Variant links:
Genes affected
RAP1B (HGNC:9857): (RAP1B, member of RAS oncogene family) This gene encodes a member of the RAS-like small GTP-binding protein superfamily. Members of this family regulate multiple cellular processes including cell adhesion and growth and differentiation. This protein localizes to cellular membranes and has been shown to regulate integrin-mediated cell signaling. This protein also plays a role in regulating outside-in signaling in platelets. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 3, 5, 6 and 9. [provided by RefSeq, Oct 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a chain Ras-related protein Rap-1b (size 180) in uniprot entity RAP1B_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001010942.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAP1BNM_001010942.3 linkc.104C>T p.Thr35Met missense_variant Exon 3 of 8 ENST00000250559.14 NP_001010942.1 P61224-1A0A024RB87

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAP1BENST00000250559.14 linkc.104C>T p.Thr35Met missense_variant Exon 3 of 8 1 NM_001010942.3 ENSP00000250559.9 P61224-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151636
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000961
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1403848
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
698216
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151636
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74020
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000961
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 09, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21098103) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;D;.;D;D;D;D;D;.;D;D;.;.;.;.;.;D;D;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
.;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.5
H;H;.;.;.;H;H;.;.;.;.;H;.;H;.;.;.;.;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-5.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0040
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.85
P;P;.;.;.;P;P;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.79
MutPred
0.85
Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);Loss of phosphorylation at T35 (P = 0.0545);
MVP
0.89
MPC
2.3
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.73
gMVP
0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1873734151; hg19: chr12-69044226; COSMIC: COSV51668624; COSMIC: COSV51668624; API