1-111697431-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002884.4(RAP1A):c.127-10G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAP1A NM_002884.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001279
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.988

Genes affected

RAP1A (HGNC:9855): (RAP1A, member of RAS oncogene family) This gene encodes a member of the Ras family of small GTPases. The encoded protein undergoes a change in conformational state and activity, depending on whether it is bound to GTP or GDP. This protein is activated by several types of guanine nucleotide exchange factors (GEFs), and inactivated by two groups of GTPase-activating proteins (GAPs). The activation status of the encoded protein is therefore affected by the balance of intracellular levels of GEFs and GAPs. The encoded protein regulates signaling pathways that affect cell proliferation and adhesion, and may play a role in tumor malignancy. Pseudogenes of this gene have been defined on chromosomes 14 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

INKA2 (HGNC:28045): (inka box actin regulator 2) Enables protein kinase binding activity. Predicted to be involved in negative regulation of catalytic activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-111697431-G-T is Benign according to our data. Variant chr1-111697431-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 769526.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 680 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1A	NM_002884.4	c.127-10G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000369709.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1A	ENST00000369709.4	c.127-10G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002884.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 154 AN: 117652 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000829

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00658

Gnomad MID AF: 0.00403

Gnomad NFE AF: 0.000815

Gnomad OTH AF: 0.00187

GnomAD3 exomes AF: 0.00472 AC: 680 AN: 144188 Hom.: 0 AF XY: 0.00449 AC XY: 349 AN XY: 77706

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00758

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.00352

Gnomad SAS exome AF: 0.00660

Gnomad FIN exome AF: 0.00785

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00581

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00120 AC: 1621 AN: 1352250 Hom.: 0 Cov.: 34 AF XY: 0.00119 AC XY: 798 AN XY: 669726

Gnomad4 AFR exome AF: 0.00415

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.00266

Gnomad4 EAS exome AF: 0.000385

Gnomad4 SAS exome AF: 0.00321

Gnomad4 FIN exome AF: 0.00423

Gnomad4 NFE exome AF: 0.000470

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00132 AC: 155 AN: 117702 Hom.: 0 Cov.: 30 AF XY: 0.00165 AC XY: 94 AN XY: 56990

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.000827

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00658

Gnomad4 NFE AF: 0.000815

Gnomad4 OTH AF: 0.00246

Alfa AF: 0.00427 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.090
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs748245059; hg19: chr1-112240053;