1-111695594-A-G

Position:

• chr1-111695594-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002884.4(RAP1A):​c.126+185A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0404 in 152,224 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.040 (142 hom., cov: 33)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.930

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-111695594-A-G is Benign according to our data. Variant chr1-111695594-A-G is described in ClinVar as [Benign]. Clinvar id is 1222741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAP1A	NM_002884.4	c.126+185A>G		intron_variant		ENST00000369709.4	NP_002875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAP1A	ENST00000369709.4	c.126+185A>G		intron_variant		1	NM_002884.4	ENSP00000358723	P1

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6152 AN: 152106 Hom.: 142 Cov.: 33

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.0785

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0529

Gnomad OTH AF: 0.0412

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

GnomAD4 genome AF: 0.0404 AC: 6148 AN: 152224 Hom.: 142 Cov.: 33 AF XY: 0.0406 AC XY: 3023 AN XY: 74430

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.0323

Gnomad4 ASJ AF: 0.0533

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.0788

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0529

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0426 Hom.: 11

Bravo AF: 0.0363

Asia WGS AF: 0.0470 AC: 163 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0070
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs12723732; hg19: chr1-112238216;