dbSNP rs10489469: RAP1A:c.57+45G>T (chr1-111691462-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.127

Variant links:

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]

RAP1A links:

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]

INKA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
RAP1A	NM_002884.4 link	c.57+45G>T		intron_variant	Intron 2 of 7	ENST00000369709.4	NP_002875.1	P62834A8KAH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAP1A	ENST00000369709.4 link	c.57+45G>T		intron_variant	Intron 2 of 7	1	NM_002884.4	ENSP00000358723.3		P62834

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

19029

AN:

152030

Hom.:

1532

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.160

AC XY:

110073

AN XY:

689962

show subpopulations

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.:

AF XY:

0.127

AC XY:

9435

AN XY:

74388

show subpopulations

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over