NM_001010942.3:c.57+129T>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001010942.3(RAP1B):​c.57+129T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 827,046 control chromosomes in the GnomAD database, including 34,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4768 hom., cov: 31)
  • Exomes 𝑓: 0.29 (30038 hom.)
• Consequence: RAP1B NM_001010942.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.40
• Publications: 4 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-68648910-T-G is Benign according to our data. Variant chr12-68648910-T-G is described in ClinVar as Benign. ClinVar VariationId is 1283372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.317 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.57+129T>G		intron	N/A	NP_001010942.1	P61224-1
	RAP1B	NM_015646.6		c.57+129T>G		intron	N/A	NP_056461.1	P61224-1
	RAP1B	NM_001251921.2		c.57+129T>G		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>G		intron	N/A	ENSP00000250559.9	P61224-1
	RAP1B	ENST00000393436.9	TSL:1	c.57+129T>G		intron	N/A	ENSP00000377085.5	P61224-1
	RAP1B	ENST00000541216.1	TSL:1	c.57+129T>G		intron	N/A	ENSP00000443851.1	F5H7Y6

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34713 AN: 151990 Hom.: 4774 Cov.: 31

Gnomad AFR AF: 0.0886

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.288 AC: 194078 AN: 674938 Hom.: 30038 Cov.: 9 AF XY: 0.282 AC XY: 96748 AN XY: 343512

African (AFR) AF: 0.0846 AC: 1342 AN: 15860

American (AMR) AF: 0.186 AC: 2981 AN: 15990

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 2984 AN: 14744

East Asian (EAS) AF: 0.133 AC: 4130 AN: 31096

South Asian (SAS) AF: 0.126 AC: 5440 AN: 43194

European-Finnish (FIN) AF: 0.341 AC: 14370 AN: 42134

Middle Eastern (MID) AF: 0.162 AC: 618 AN: 3824

European-Non Finnish (NFE) AF: 0.323 AC: 153679 AN: 475390

Other (OTH) AF: 0.261 AC: 8534 AN: 32706

GnomAD4 genome AF: 0.228 AC: 34706 AN: 152108 Hom.: 4768 Cov.: 31 AF XY: 0.224 AC XY: 16691 AN XY: 74356

African (AFR) AF: 0.0884 AC: 3672 AN: 41546

American (AMR) AF: 0.190 AC: 2895 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 746 AN: 3472

East Asian (EAS) AF: 0.122 AC: 630 AN: 5184

South Asian (SAS) AF: 0.117 AC: 563 AN: 4818

European-Finnish (FIN) AF: 0.342 AC: 3608 AN: 10550

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21771 AN: 67952

Other (OTH) AF: 0.220 AC: 464 AN: 2110

Alfa AF: 0.278 Hom.: 2970

Bravo AF: 0.211

Asia WGS AF: 0.124 AC: 431 AN: 3478

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	-0.35
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs3213921; hg19: chr12-69042690;