1-111699173-A-G

Variant names:

• chr1-111699173-A-G
• rs558989
• NM_002884.4:c.183+1676A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002884.4(RAP1A):​c.183+1676A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 151,076 control chromosomes in the GnomAD database, including 1,535 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1535 hom., cov: 30)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAP1A	NM_002884.4	c.183+1676A>G		intron_variant	Intron 4 of 7	ENST00000369709.4	NP_002875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAP1A	ENST00000369709.4	c.183+1676A>G		intron_variant	Intron 4 of 7	1	NM_002884.4	ENSP00000358723.3

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20005 AN: 150958 Hom.: 1537 Cov.: 30

Gnomad AFR AF: 0.0808

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.142

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.132 AC: 20008 AN: 151076 Hom.: 1535 Cov.: 30 AF XY: 0.135 AC XY: 9963 AN XY: 73806

African (AFR) AF: 0.0808 AC: 3326 AN: 41140

American (AMR) AF: 0.190 AC: 2883 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 582 AN: 3464

East Asian (EAS) AF: 0.211 AC: 1082 AN: 5136

South Asian (SAS) AF: 0.113 AC: 543 AN: 4786

European-Finnish (FIN) AF: 0.182 AC: 1876 AN: 10304

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9356 AN: 67752

Other (OTH) AF: 0.140 AC: 294 AN: 2100

Alfa AF: 0.135 Hom.: 4645

Bravo AF: 0.132

Asia WGS AF: 0.167 AC: 579 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.3
DANN	Benign	0.85
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs558989; hg19: chr1-112241795;