1-111697416-CTTTTTT-CTTTTT

Variant names:

• chr1-111697416-CT-C
• rs34219774
• NM_002884.4:c.127-11delT

Variant summary

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

The NM_002884.4(RAP1A):​c.127-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 142,238 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), 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: 𝑓 0.0027 (0 hom., cov: 22)
  • Exomes 𝑓: 0.19 (0 hom.)
  • Failed GnomAD Quality Control
• 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: 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.127-11delT		intron	N/A	NP_002875.1	P62834
	RAP1A	NM_001010935.3		c.127-11delT		intron	N/A	NP_001010935.1	P62834
	RAP1A	NM_001291896.3		c.127-11delT		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.127-24delT		intron	N/A	ENSP00000358723.3	P62834
	RAP1A	ENST00000356415.5	TSL:1	c.127-24delT		intron	N/A	ENSP00000348786.1	P62834
	RAP1A	ENST00000687939.1		c.127-24delT		intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 384 AN: 142198 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000768

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00182

Gnomad SAS AF: 0.000447

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00257

GnomAD2 exomes AF: 0.299 AC: 49636 AN: 165996 AF XY: 0.300

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.316

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.303

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.185 AC: 178089 AN: 961320 Hom.: 0 Cov.: 0 AF XY: 0.191 AC XY: 92721 AN XY: 485688

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

African (AFR) AF: 0.126 AC: 3191 AN: 25336

American (AMR) AF: 0.240 AC: 8351 AN: 34760

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 4707 AN: 19426

East Asian (EAS) AF: 0.240 AC: 7294 AN: 30368

South Asian (SAS) AF: 0.237 AC: 15341 AN: 64856

European-Finnish (FIN) AF: 0.223 AC: 9242 AN: 41368

Middle Eastern (MID) AF: 0.188 AC: 797 AN: 4232

European-Non Finnish (NFE) AF: 0.173 AC: 120947 AN: 699094

Other (OTH) AF: 0.196 AC: 8219 AN: 41880

⚠️ 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: 0.00271 AC: 386 AN: 142238 Hom.: 0 Cov.: 22 AF XY: 0.00304 AC XY: 210 AN XY: 68986

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

African (AFR) AF: 0.000767 AC: 30 AN: 39124

American (AMR) AF: 0.00261 AC: 37 AN: 14164

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 5 AN: 3316

East Asian (EAS) AF: 0.00182 AC: 9 AN: 4940

South Asian (SAS) AF: 0.000673 AC: 3 AN: 4460

European-Finnish (FIN) AF: 0.0114 AC: 96 AN: 8426

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

European-Non Finnish (NFE) AF: 0.00309 AC: 200 AN: 64686

Other (OTH) AF: 0.00306 AC: 6 AN: 1962

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0905 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

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: rs34219774; hg19: chr1-112240038; COSMIC: COSV62727289;