rs10489469

chr1-111691462-G-T

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+45G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,530,982 control chromosomes in the GnomAD database, including 19,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1538 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18198 hom.)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.127

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=-0.81).
• BP6: Variant 1-111691462-G-T is Benign according to our data. Variant chr1-111691462-G-T is described in ClinVar as [Benign]. Clinvar id is 1230259.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1A	NM_002884.4	c.57+45G>T		intron_variant		ENST00000369709.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1A	ENST00000369709.4	c.57+45G>T		intron_variant		1	NM_002884.4	P1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19029 AN: 152030 Hom.: 1532 Cov.: 32

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.157 AC: 38500 AN: 244974 Hom.: 3220 AF XY: 0.160 AC XY: 21137 AN XY: 132326

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.159 AC: 219064 AN: 1378834 Hom.: 18198 Cov.: 23 AF XY: 0.160 AC XY: 110073 AN XY: 689962

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.125 AC: 19043 AN: 152148 Hom.: 1538 Cov.: 32 AF XY: 0.127 AC XY: 9435 AN XY: 74388

Gnomad4 AFR AF: 0.0311

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.136

Alfa AF: 0.154 Hom.: 2584

Bravo AF: 0.115

Asia WGS AF: 0.193 AC: 668 AN: 3478

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

May 15, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	13
Dann	Benign	0.58

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: rs10489469; hg19: chr1-112234084; COSMIC: COSV62728949;