Genetic Variant RAP1A:c.127-10G>T (chr1-111697431-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_002884.4(RAP1A):c.127-10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAP1A
NM_002884.4 intron

Scores

Splicing: ADA: 0.00001279

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.988

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-111697431-G-T is Benign according to our data. Variant chr1-111697431-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 769526.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAP1A	NM_002884.4	MANE Select	c.127-10G>T	intron	N/A	NP_002875.1	P62834
RAP1A	NM_001010935.3		c.127-10G>T	intron	N/A	NP_001010935.1	P62834
RAP1A	NM_001291896.3		c.127-10G>T	intron	N/A	NP_001278825.1	P62834

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAP1A	ENST00000369709.4	TSL:1 MANE Select	c.127-10G>T	intron	N/A	ENSP00000358723.3	P62834
RAP1A	ENST00000356415.5	TSL:1	c.127-10G>T	intron	N/A	ENSP00000348786.1	P62834
RAP1A	ENST00000687939.1		c.127-10G>T	intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

154

AN:

117652

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000829

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00658

Gnomad MID

AF:

0.00403

Gnomad NFE

AF:

0.000815

Gnomad OTH

AF:

0.00187

GnomAD2 exomes

AF:

0.00472

AC:

680

AN:

144188

AF XY:

0.00449

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00758

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.00352

Gnomad FIN exome

AF:

0.00785

Gnomad NFE exome

AF:

0.00326

Gnomad OTH exome

AF:

0.00581

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00120

AC:

1621

AN:

1352250

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

798

AN XY:

669726

show subpopulations

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

African (AFR)

AF:

0.00415

AC:

120

AN:

28950

American (AMR)

AF:

0.0129

AC:

427

AN:

33094

Ashkenazi Jewish (ASJ)

AF:

0.00266

AC:

AN:

22974

East Asian (EAS)

AF:

0.000385

AC:

AN:

36362

South Asian (SAS)

AF:

0.00321

AC:

220

AN:

68474

European-Finnish (FIN)

AF:

0.00423

AC:

176

AN:

41610

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

5144

European-Non Finnish (NFE)

AF:

0.000470

AC:

498

AN:

1060272

Other (OTH)

AF:

0.00157

AC:

AN:

55370

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

137

274

411

548

685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00132

AC:

155

AN:

117702

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

AN XY:

56990

show subpopulations

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

African (AFR)

AF:

0.00149

AC:

AN:

29626

American (AMR)

AF:

0.000827

AC:

AN:

12088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2914

East Asian (EAS)

AF:

0.00

AC:

AN:

4324

South Asian (SAS)

AF:

0.00105

AC:

AN:

3822

European-Finnish (FIN)

AF:

0.00658

AC:

AN:

7146

Middle Eastern (MID)

AF:

0.00431

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.000815

AC:

AN:

55224

Other (OTH)

AF:

0.00246

AC:

AN:

1624

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.285

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00427

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.090

(source)

DANN

Benign

0.79

PhyloP100

-0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over