Genetic Variant RAP1B:p.Thr35Met (chr12-68650446-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

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

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]

RAP1B links:

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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
RAP1B	NM_001010942.3 link	c.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
RAP1B	ENST00000250559.14 link	c.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:

AN:

151636

Hom.:

Cov.:

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:

AN:

1403848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

AN:

151636

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

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

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

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

MutationAssessor

Pathogenic

4.5

H;H;.;.;.;H;H;.;.;.;.;H;.;H;.;.;.;.;.

PrimateAI

Pathogenic

0.80

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over