12-68650501-G-T

Variant names:

• chr12-68650501-G-T
• rs12310406
• NM_001010942.3:c.126+33G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001010942.3(RAP1B):​c.126+33G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,396,192 control chromosomes in the GnomAD database, including 1,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (650 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (459 hom.)
• Consequence: RAP1B NM_001010942.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.364
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-68650501-G-T is Benign according to our data. Variant chr12-68650501-G-T is described in ClinVar as Benign. ClinVar VariationId is 1267109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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.126+33G>T		intron	N/A	NP_001010942.1	P61224-1
	RAP1B	NM_015646.6		c.126+33G>T		intron	N/A	NP_056461.1	P61224-1
	RAP1B	NM_001251921.2		c.126+33G>T		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.126+33G>T		intron	N/A	ENSP00000250559.9	P61224-1
	RAP1B	ENST00000393436.9	TSL:1	c.126+33G>T		intron	N/A	ENSP00000377085.5	P61224-1
	RAP1B	ENST00000541216.1	TSL:1	c.126+33G>T		intron	N/A	ENSP00000443851.1	F5H7Y6

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7788 AN: 151850 Hom.: 651 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0264

GnomAD2 exomes AF: 0.0121 AC: 1859 AN: 153666 AF XY: 0.00842

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.00947

Gnomad ASJ exome AF: 0.000668

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.00757

GnomAD4 exome AF: 0.00467 AC: 5812 AN: 1244224 Hom.: 459 Cov.: 22 AF XY: 0.00412 AC XY: 2552 AN XY: 619708

African (AFR) AF: 0.183 AC: 4572 AN: 24984

American (AMR) AF: 0.0121 AC: 269 AN: 22310

Ashkenazi Jewish (ASJ) AF: 0.000433 AC: 9 AN: 20766

East Asian (EAS) AF: 0.00 AC: 0 AN: 33776

South Asian (SAS) AF: 0.000424 AC: 27 AN: 63654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48420

Middle Eastern (MID) AF: 0.00886 AC: 32 AN: 3612

European-Non Finnish (NFE) AF: 0.000328 AC: 320 AN: 975860

Other (OTH) AF: 0.0115 AC: 583 AN: 50842

GnomAD4 genome AF: 0.0513 AC: 7800 AN: 151968 Hom.: 650 Cov.: 32 AF XY: 0.0503 AC XY: 3738 AN XY: 74282

African (AFR) AF: 0.178 AC: 7392 AN: 41452

American (AMR) AF: 0.0199 AC: 304 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

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

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67950

Other (OTH) AF: 0.0262 AC: 55 AN: 2102

Alfa AF: 0.0320 Hom.: 86

Bravo AF: 0.0595

Asia WGS AF: 0.00925 AC: 33 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.3
DANN	Benign	0.76
PhyloP100		-0.36
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: rs12310406; hg19: chr12-69044281;