rs6573

Positions:

• chr1-111712767-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002884.4(RAP1A):​c.*366C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,412 control chromosomes in the GnomAD database, including 1,552 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1543 hom., cov: 32)
  • Exomes 𝑓: 0.20 (9 hom.)
• Consequence: RAP1A NM_002884.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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=-0.36).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAP1A	NM_002884.4	c.*366C>A		3_prime_UTR_variant	8/8	ENST00000369709.4	NP_002875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAP1A	ENST00000369709.4	c.*366C>A		3_prime_UTR_variant	8/8	1	NM_002884.4	ENSP00000358723	P1
RAP1A	ENST00000356415.5	c.*366C>A		3_prime_UTR_variant	8/8	1		ENSP00000348786	P1
RAP1A	ENST00000687939.1	c.*366C>A		3_prime_UTR_variant	9/9			ENSP00000509234	P1
INKA2	ENST00000527570.1	n.219-26084G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19174 AN: 151864 Hom.: 1537 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.195 AC: 84 AN: 430 Hom.: 9 Cov.: 0 AF XY: 0.198 AC XY: 51 AN XY: 258

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.126 AC: 19190 AN: 151982 Hom.: 1543 Cov.: 32 AF XY: 0.128 AC XY: 9504 AN XY: 74282

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.138

Alfa AF: 0.152 Hom.: 1779

Bravo AF: 0.116

Asia WGS AF: 0.193 AC: 666 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6573; hg19: chr1-112255389;