chr1-111707860-G-A

Variant names:

• chr1-111707860-G-A
• rs4484921
• NM_002884.4:c.469-1289G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002884.4(RAP1A):​c.469-1289G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 152,280 control chromosomes in the GnomAD database, including 37 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 0.019 (37 hom., cov: 33)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.426
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2832/152280) while in subpopulation NFE AF = 0.0265 (1801/68004). AF 95% confidence interval is 0.0255. There are 37 homozygotes in GnomAd4. There are 1471 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2832 AD gene.

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.469-1289G>A		intron	N/A	NP_002875.1
	RAP1A	NM_001010935.3		c.469-1289G>A		intron	N/A	NP_001010935.1
	RAP1A	NM_001291896.3		c.469-1289G>A		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.469-1289G>A		intron	N/A	ENSP00000358723.3
	RAP1A	ENST00000356415.5	TSL:1	c.469-1289G>A		intron	N/A	ENSP00000348786.1
	RAP1A	ENST00000687939.1		c.469-1289G>A		intron	N/A	ENSP00000509234.1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2832 AN: 152162 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0265

Gnomad OTH AF: 0.0148

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0186 AC: 2832 AN: 152280 Hom.: 37 Cov.: 33 AF XY: 0.0198 AC XY: 1471 AN XY: 74458

African (AFR) AF: 0.00450 AC: 187 AN: 41564

American (AMR) AF: 0.0136 AC: 208 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4828

European-Finnish (FIN) AF: 0.0442 AC: 469 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0265 AC: 1801 AN: 68004

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0233 Hom.: 10

Bravo AF: 0.0157

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.6
DANN	Benign	0.77
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

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: rs4484921; hg19: chr1-112250482;