12-68648910-T-C

Variant names:

• chr12-68648910-T-C
• rs3213921
• NM_001010942.3:c.57+129T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010942.3(RAP1B):​c.57+129T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 676,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RAP1B NM_001010942.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).

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.57+129T>C		intron	N/A	NP_001010942.1	P61224-1
	RAP1B	NM_015646.6		c.57+129T>C		intron	N/A	NP_056461.1	P61224-1
	RAP1B	NM_001251921.2		c.57+129T>C		intron	N/A	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.57+129T>C		intron	N/A	ENSP00000250559.9	P61224-1
	RAP1B	ENST00000393436.9	TSL:1	c.57+129T>C		intron	N/A	ENSP00000377085.5	P61224-1
	RAP1B	ENST00000541216.1	TSL:1	c.57+129T>C		intron	N/A	ENSP00000443851.1	F5H7Y6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000148 AC: 1 AN: 676418 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 344204

African (AFR) AF: 0.00 AC: 0 AN: 15878

American (AMR) AF: 0.00 AC: 0 AN: 15996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14756

East Asian (EAS) AF: 0.0000321 AC: 1 AN: 31112

South Asian (SAS) AF: 0.00 AC: 0 AN: 43228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3826

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 476658

Other (OTH) AF: 0.00 AC: 0 AN: 32752

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.82
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs3213921; hg19: chr12-69042690;