12-68652044-C-G

Variant names:

• chr12-68652044-C-G
• NM_001010942.3:c.176C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001010942.3(RAP1B):​c.176C>G​(p.Ala59Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAP1B NM_001010942.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.54

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]

ACMG classification

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, 0.899
• PP5: Variant 12-68652044-C-G is Pathogenic according to our data. Variant chr12-68652044-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1300148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAP1B	NM_001010942.3	c.176C>G	p.Ala59Gly	missense_variant	Exon 4 of 8	ENST00000250559.14	NP_001010942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAP1B	ENST00000250559.14	c.176C>G	p.Ala59Gly	missense_variant	Exon 4 of 8	1	NM_001010942.3	ENSP00000250559.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Pathogenic:1

Sep 03, 2021

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies Pathogenic:1

Mar 06, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;.;D;D;D;D;D;.;.;D;D;.;.;D;D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;.;T;T;T;.;T;T;T;T;D;T;T;D;T;D;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;M;M;.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.68	P;P;.;.;.;P;P;.;.;.;.;.;.;.;.;.;.
Vest4		0.72
MutPred		0.77		Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);.;Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);Loss of stability (P = 0.0706);
MVP		0.93
MPC		2.2
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.94
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-69045824;