1-111691446-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002884.4(RAP1A):c.57+29T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,572,560 control chromosomes in the GnomAD database, including 16,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1409 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14638 hom.)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.563

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-111691446-T-A is Benign according to our data. Variant chr1-111691446-T-A is described in ClinVar as [Benign]. Clinvar id is 1249165.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1A	NM_002884.4	c.57+29T>A		intron_variant		ENST00000369709.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1A	ENST00000369709.4	c.57+29T>A		intron_variant		1	NM_002884.4	P1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18028 AN: 152078 Hom.: 1411 Cov.: 32

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.157 AC: 39208 AN: 249544 Hom.: 3683 AF XY: 0.152 AC XY: 20504 AN XY: 134848

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.136 AC: 193691 AN: 1420364 Hom.: 14638 Cov.: 27 AF XY: 0.136 AC XY: 96317 AN XY: 709006

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.118 AC: 18020 AN: 152196 Hom.: 1409 Cov.: 32 AF XY: 0.121 AC XY: 9028 AN XY: 74400

Gnomad4 AFR AF: 0.0348

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.210

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.129

Alfa AF: 0.141 Hom.: 296

Bravo AF: 0.117

Asia WGS AF: 0.162 AC: 562 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	14
Dann	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs506070; hg19: chr1-112234068; COSMIC: COSV62727778;