1-111695324-CTT-CTTT

Variant names:

• chr1-111695324-C-CT
• rs552633846
• NM_002884.4:c.58-8dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002884.4(RAP1A):​c.58-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,455,060 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: RAP1A NM_002884.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.394
• 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: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	NM_002884.4	MANE Select	c.58-8dupT		splice_region intron	N/A	NP_002875.1	P62834
	RAP1A	NM_001010935.3		c.58-8dupT		splice_region intron	N/A	NP_001010935.1	P62834
	RAP1A	NM_001291896.3		c.58-8dupT		splice_region intron	N/A	NP_001278825.1	P62834

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	ENST00000369709.4	TSL:1 MANE Select	c.58-17_58-16insT		intron	N/A	ENSP00000358723.3	P62834
	RAP1A	ENST00000356415.5	TSL:1	c.58-17_58-16insT		intron	N/A	ENSP00000348786.1	P62834
	RAP1A	ENST00000687939.1		c.58-17_58-16insT		intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 151004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00160 AC: 274 AN: 171104 AF XY: 0.00150

Gnomad AFR exome AF: 0.00238

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00225

Gnomad EAS exome AF: 0.00356

Gnomad FIN exome AF: 0.000303

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00108 AC: 1410 AN: 1304056 Hom.: 0 Cov.: 28 AF XY: 0.00107 AC XY: 698 AN XY: 650378

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00130 AC: 36 AN: 27734

American (AMR) AF: 0.00221 AC: 61 AN: 27586

Ashkenazi Jewish (ASJ) AF: 0.00139 AC: 32 AN: 23070

East Asian (EAS) AF: 0.00160 AC: 55 AN: 34272

South Asian (SAS) AF: 0.00150 AC: 105 AN: 70110

European-Finnish (FIN) AF: 0.000688 AC: 35 AN: 50884

Middle Eastern (MID) AF: 0.000885 AC: 4 AN: 4518

European-Non Finnish (NFE) AF: 0.00101 AC: 1023 AN: 1012162

Other (OTH) AF: 0.00110 AC: 59 AN: 53720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 151004 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73678

African (AFR) AF: 0.00 AC: 0 AN: 41100

American (AMR) AF: 0.0000661 AC: 1 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67718

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00400 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39

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: rs552633846; hg19: chr1-112237946;