chr1-111697416-CTT-C

Variant names:

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

Variant summary

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

The NM_002884.4(RAP1A):​c.127-12_127-11delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,479,382 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. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 22)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.828
• 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.127-12_127-11delTT		intron	N/A	NP_002875.1	P62834
	RAP1A	NM_001010935.3		c.127-12_127-11delTT		intron	N/A	NP_001010935.1	P62834
	RAP1A	NM_001291896.3		c.127-12_127-11delTT		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.127-24_127-23delTT		intron	N/A	ENSP00000358723.3	P62834
	RAP1A	ENST00000356415.5	TSL:1	c.127-24_127-23delTT		intron	N/A	ENSP00000348786.1	P62834
	RAP1A	ENST00000687939.1		c.127-24_127-23delTT		intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes AF: 0.000457 AC: 65 AN: 142220 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000424

Gnomad ASJ AF: 0.000301

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000386

Gnomad OTH AF: 0.00102

GnomAD2 exomes AF: 0.0594 AC: 9867 AN: 165996 AF XY: 0.0612

Gnomad AFR exome AF: 0.0341

Gnomad AMR exome AF: 0.0659

Gnomad ASJ exome AF: 0.0607

Gnomad EAS exome AF: 0.0661

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.0597

Gnomad OTH exome AF: 0.0629

GnomAD4 exome AF: 0.0134 AC: 17983 AN: 1337116 Hom.: 0 AF XY: 0.0146 AC XY: 9659 AN XY: 662880

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

African (AFR) AF: 0.0107 AC: 321 AN: 30042

American (AMR) AF: 0.0415 AC: 1493 AN: 35940

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 630 AN: 22884

East Asian (EAS) AF: 0.0223 AC: 778 AN: 34890

South Asian (SAS) AF: 0.0340 AC: 2506 AN: 73622

European-Finnish (FIN) AF: 0.0309 AC: 1366 AN: 44266

Middle Eastern (MID) AF: 0.0148 AC: 76 AN: 5146

European-Non Finnish (NFE) AF: 0.00955 AC: 9892 AN: 1035580

Other (OTH) AF: 0.0168 AC: 921 AN: 54746

⚠️ 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: 0.000457 AC: 65 AN: 142266 Hom.: 0 Cov.: 22 AF XY: 0.000464 AC XY: 32 AN XY: 69016

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

African (AFR) AF: 0.000102 AC: 4 AN: 39134

American (AMR) AF: 0.000424 AC: 6 AN: 14154

Ashkenazi Jewish (ASJ) AF: 0.000301 AC: 1 AN: 3318

East Asian (EAS) AF: 0.00 AC: 0 AN: 4946

South Asian (SAS) AF: 0.00 AC: 0 AN: 4466

European-Finnish (FIN) AF: 0.00321 AC: 27 AN: 8422

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

European-Non Finnish (NFE) AF: 0.000386 AC: 25 AN: 64700

Other (OTH) AF: 0.00102 AC: 2 AN: 1966

⚠️ 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: 0.0338 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.83
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;