NM_002884.4:c.57+45G>T

Variant names:

• chr1-111691462-G-T
• rs10489469
• NM_002884.4:c.57+45G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.127
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002884.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	NM_002884.4	MANE Select	c.57+45G>T		intron	N/A	NP_002875.1
	RAP1A	NM_001010935.3		c.57+45G>T		intron	N/A	NP_001010935.1
	RAP1A	NM_001291896.3		c.57+45G>T		intron	N/A	NP_001278825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	ENST00000369709.4	TSL:1 MANE Select	c.57+45G>T		intron	N/A	ENSP00000358723.3
	RAP1A	ENST00000356415.5	TSL:1	c.57+45G>T		intron	N/A	ENSP00000348786.1
	RAP1A	ENST00000687939.1		c.57+45G>T		intron	N/A	ENSP00000509234.1

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

GnomAD2 exomes AF: 0.157 AC: 38500 AN: 244974 AF XY: 0.160

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 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

African (AFR) AF: 0.0242 AC: 762 AN: 31490

American (AMR) AF: 0.150 AC: 6491 AN: 43288

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4840 AN: 25448

East Asian (EAS) AF: 0.118 AC: 4612 AN: 39194

South Asian (SAS) AF: 0.172 AC: 14309 AN: 83372

European-Finnish (FIN) AF: 0.213 AC: 11355 AN: 53272

Middle Eastern (MID) AF: 0.0999 AC: 559 AN: 5594

European-Non Finnish (NFE) AF: 0.161 AC: 167380 AN: 1039538

Other (OTH) AF: 0.152 AC: 8756 AN: 57638

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

African (AFR) AF: 0.0311 AC: 1291 AN: 41536

American (AMR) AF: 0.132 AC: 2017 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 658 AN: 3470

East Asian (EAS) AF: 0.146 AC: 756 AN: 5180

South Asian (SAS) AF: 0.175 AC: 844 AN: 4820

European-Finnish (FIN) AF: 0.218 AC: 2305 AN: 10572

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10733 AN: 67972

Other (OTH) AF: 0.136 AC: 287 AN: 2112

Alfa AF: 0.150 Hom.: 3110

Bravo AF: 0.115

Asia WGS AF: 0.193 AC: 668 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.81
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		-0.13
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: rs10489469; hg19: chr1-112234084; COSMIC: COSV62728949;