chr1-111695324-CT-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_002884.4(RAP1A):​c.58-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000285 in 1,464,444 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: RAP1A NM_002884.4 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 1-111695324-CT-C is Benign according to our data. Variant chr1-111695324-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3052287.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 54 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	NM_002884.4	MANE Select	c.58-8delT		splice_region intron	N/A	NP_002875.1	P62834
	RAP1A	NM_001010935.3		c.58-8delT		splice_region intron	N/A	NP_001010935.1	P62834
	RAP1A	NM_001291896.3		c.58-8delT		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.58-16delT		intron	N/A	ENSP00000358723.3	P62834
	RAP1A	ENST00000356415.5	TSL:1	c.58-16delT		intron	N/A	ENSP00000348786.1	P62834
	RAP1A	ENST00000687939.1		c.58-16delT		intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes AF: 0.000351 AC: 53 AN: 151010 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000637 AC: 109 AN: 171104 AF XY: 0.000537

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.000265

Gnomad EAS exome AF: 0.00110

Gnomad FIN exome AF: 0.0000506

Gnomad NFE exome AF: 0.000515

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.000276 AC: 363 AN: 1313320 Hom.: 0 Cov.: 28 AF XY: 0.000273 AC XY: 179 AN XY: 654834

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

African (AFR) AF: 0.00147 AC: 41 AN: 27934

American (AMR) AF: 0.000542 AC: 15 AN: 27694

Ashkenazi Jewish (ASJ) AF: 0.0000860 AC: 2 AN: 23244

East Asian (EAS) AF: 0.000405 AC: 14 AN: 34528

South Asian (SAS) AF: 0.000326 AC: 23 AN: 70540

European-Finnish (FIN) AF: 0.0000392 AC: 2 AN: 51080

Middle Eastern (MID) AF: 0.000440 AC: 2 AN: 4548

European-Non Finnish (NFE) AF: 0.000246 AC: 251 AN: 1019700

Other (OTH) AF: 0.000241 AC: 13 AN: 54052

⚠️ 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: 0.000357 AC: 54 AN: 151124 Hom.: 1 Cov.: 32 AF XY: 0.000420 AC XY: 31 AN XY: 73806

African (AFR) AF: 0.000994 AC: 41 AN: 41228

American (AMR) AF: 0.000661 AC: 10 AN: 15140

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

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

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

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67710

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000382

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	RAP1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;