1-111695324-CTT-CTTTT

Variant names:

• chr1-111695324-C-CTT
• rs552633846
• NM_002884.4:c.58-9_58-8dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002884.4(RAP1A):​c.58-9_58-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000038 in 1,314,582 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.58-9_58-8dupTT		splice_region intron	N/A	NP_002875.1	P62834
	RAP1A	NM_001010935.3		c.58-9_58-8dupTT		splice_region intron	N/A	NP_001010935.1	P62834
	RAP1A	NM_001291896.3		c.58-9_58-8dupTT		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_58-16insTT		intron	N/A	ENSP00000358723.3	P62834
	RAP1A	ENST00000356415.5	TSL:1	c.58-17_58-16insTT		intron	N/A	ENSP00000348786.1	P62834
	RAP1A	ENST00000687939.1		c.58-17_58-16insTT		intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000175 AC: 3 AN: 171104 AF XY: 0.0000105

Gnomad AFR exome AF: 0.0000950

Gnomad AMR exome AF: 0.0000632

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000257

GnomAD4 exome AF: 0.00000380 AC: 5 AN: 1314582 Hom.: 0 Cov.: 28 AF XY: 0.00000153 AC XY: 1 AN XY: 655534

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

African (AFR) AF: 0.00 AC: 0 AN: 27962

American (AMR) AF: 0.0000360 AC: 1 AN: 27750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23262

East Asian (EAS) AF: 0.00 AC: 0 AN: 34574

South Asian (SAS) AF: 0.00 AC: 0 AN: 70670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4548

European-Non Finnish (NFE) AF: 0.00000294 AC: 3 AN: 1020580

Other (OTH) AF: 0.0000185 AC: 1 AN: 54114

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs552633846; hg19: chr1-112237946;