Genetic Variant NM_002884.4:c.469-1289G>A (chr1-111707860-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002884.4(RAP1A):c.469-1289G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 152,280 control chromosomes in the GnomAD database, including 37 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 0.019 ( 37 hom., cov: 33)

Consequence

RAP1A
NM_002884.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.426

Publications

0 publications found

Variant links:

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]

RAP1A links:

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]

INKA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2832/152280) while in subpopulation NFE AF = 0.0265 (1801/68004). AF 95% confidence interval is 0.0255. There are 37 homozygotes in GnomAd4. There are 1471 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2832 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAP1A	NM_002884.4 link	c.469-1289G>A		intron_variant	Intron 6 of 7	ENST00000369709.4	NP_002875.1	P62834A8KAH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAP1A	ENST00000369709.4 link	c.469-1289G>A		intron_variant	Intron 6 of 7	1	NM_002884.4	ENSP00000358723.3		P62834

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2832

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00451

Gnomad AMI

AF:

0.0418

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0265

Gnomad OTH

AF:

0.0148

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

GnomAD4 genome

AF:

0.0186

AC:

2832

AN:

152280

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1471

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00450

AC:

187

AN:

41564

American (AMR)

AF:

0.0136

AC:

208

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00642

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0442

AC:

469

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0265

AC:

1801

AN:

68004

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

146

291

437

582

728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0233

Hom.:

Bravo

AF:

0.0157

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.6

(source)

DANN

Benign

0.77

PhyloP100

0.43

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over