chr12-68654543-G-A

Variant names:

• chr12-68654543-G-A
• rs73332555
• NM_001010942.3:c.324+291G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001010942.3(RAP1B):​c.324+291G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 150,588 control chromosomes in the GnomAD database, including 687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.053 (687 hom., cov: 30)
• Consequence: RAP1B NM_001010942.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.47
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 12-68654543-G-A is Benign according to our data. Variant chr12-68654543-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269724.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

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.324+291G>A		intron	N/A	NP_001010942.1	P61224-1
	RAP1B	NM_015646.6		c.324+291G>A		intron	N/A	NP_056461.1	P61224-1
	RAP1B	NM_001251921.2		c.267+291G>A		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.324+291G>A		intron	N/A	ENSP00000250559.9	P61224-1
	RAP1B	ENST00000393436.9	TSL:1	c.324+291G>A		intron	N/A	ENSP00000377085.5	P61224-1
	RAP1B	ENST00000541216.1	TSL:1	c.324+291G>A		intron	N/A	ENSP00000443851.1	F5H7Y6

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 7944 AN: 150470 Hom.: 688 Cov.: 30

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000839

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000679

Gnomad OTH AF: 0.0267

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0528 AC: 7956 AN: 150588 Hom.: 687 Cov.: 30 AF XY: 0.0519 AC XY: 3812 AN XY: 73446

African (AFR) AF: 0.184 AC: 7538 AN: 40898

American (AMR) AF: 0.0205 AC: 310 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000840 AC: 4 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10194

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000679 AC: 46 AN: 67780

Other (OTH) AF: 0.0264 AC: 55 AN: 2084

Alfa AF: 0.0491 Hom.: 83

Bravo AF: 0.0611

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.71
DANN	Benign	0.42
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs73332555; hg19: chr12-69048323;