chr1-111697416-C-CTT

Variant names:

• chr1-111697416-C-CTT
• rs34219774
• NM_002884.4:c.127-12_127-11dupTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002884.4(RAP1A):​c.127-12_127-11dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,570,240 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159
• Publications: 1 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 181 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.127-12_127-11dupTT		intron	N/A	NP_002875.1	P62834
	RAP1A	NM_001010935.3		c.127-12_127-11dupTT		intron	N/A	NP_001010935.1	P62834
	RAP1A	NM_001291896.3		c.127-12_127-11dupTT		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.127-25_127-24insTT		intron	N/A	ENSP00000358723.3	P62834
	RAP1A	ENST00000356415.5	TSL:1	c.127-25_127-24insTT		intron	N/A	ENSP00000348786.1	P62834
	RAP1A	ENST00000687939.1		c.127-25_127-24insTT		intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 180 AN: 142460 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000604

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.000236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000308

Gnomad OTH AF: 0.00102

GnomAD2 exomes AF: 0.00231 AC: 383 AN: 165996 AF XY: 0.00218

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00215

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000864 AC: 1233 AN: 1427734 Hom.: 0 Cov.: 0 AF XY: 0.000898 AC XY: 638 AN XY: 710394

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

African (AFR) AF: 0.00413 AC: 130 AN: 31496

American (AMR) AF: 0.00157 AC: 64 AN: 40816

Ashkenazi Jewish (ASJ) AF: 0.000910 AC: 23 AN: 25272

East Asian (EAS) AF: 0.000717 AC: 28 AN: 39044

South Asian (SAS) AF: 0.00162 AC: 133 AN: 81886

European-Finnish (FIN) AF: 0.000987 AC: 48 AN: 48610

Middle Eastern (MID) AF: 0.00179 AC: 10 AN: 5586

European-Non Finnish (NFE) AF: 0.000658 AC: 721 AN: 1096236

Other (OTH) AF: 0.00129 AC: 76 AN: 58788

⚠️ 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: 0.00127 AC: 181 AN: 142506 Hom.: 0 Cov.: 22 AF XY: 0.00145 AC XY: 100 AN XY: 69162

African (AFR) AF: 0.00353 AC: 138 AN: 39130

American (AMR) AF: 0.00106 AC: 15 AN: 14188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3328

East Asian (EAS) AF: 0.000606 AC: 3 AN: 4950

South Asian (SAS) AF: 0.000224 AC: 1 AN: 4466

European-Finnish (FIN) AF: 0.000236 AC: 2 AN: 8486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000308 AC: 20 AN: 64830

Other (OTH) AF: 0.00102 AC: 2 AN: 1968

Alfa AF: 0.00123 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs34219774; hg19: chr1-112240038;