12-68648735-A-G

Variant names:

• chr12-68648735-A-G
• NM_001010942.3:c.11A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001010942.3(RAP1B):​c.11A>G​(p.Tyr4Cys) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAP1B NM_001010942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, G2P
• syndromic constitutional thrombocytopenia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001010942.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.5994 (below the threshold of 3.09). Trascript score misZ: 2.7594 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, syndromic constitutional thrombocytopenia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010942.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1B	NM_001010942.3	MANE Select	c.11A>G	p.Tyr4Cys	missense	Exon 2 of 8	NP_001010942.1	P61224-1
	RAP1B	NM_015646.6		c.11A>G	p.Tyr4Cys	missense	Exon 2 of 8	NP_056461.1	P61224-1
	RAP1B	NM_001251921.2		c.11A>G	p.Tyr4Cys	missense	Exon 2 of 7	NP_001238850.1	P61224-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1B	ENST00000250559.14	TSL:1 MANE Select	c.11A>G	p.Tyr4Cys	missense	Exon 2 of 8	ENSP00000250559.9	P61224-1
	RAP1B	ENST00000393436.9	TSL:1	c.11A>G	p.Tyr4Cys	missense	Exon 2 of 8	ENSP00000377085.5	P61224-1
	RAP1B	ENST00000541216.1	TSL:1	c.11A>G	p.Tyr4Cys	missense	Exon 2 of 6	ENSP00000443851.1	F5H7Y6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.65		Gain of methylation at K5 (P = 0.0378)
MVP		0.95
MPC		3.3
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		1.0
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-69042515;