Genetic Variant NM_002884.4:c.58-48A>T (chr1-111695293-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002884.4(RAP1A):c.58-48A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,378,354 control chromosomes in the GnomAD database, including 85,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7686 hom., cov: 32)

Exomes 𝑓: 0.35 ( 77742 hom. )

Consequence

RAP1A
NM_002884.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.120

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-111695293-A-T is Benign according to our data. Variant chr1-111695293-A-T is described in ClinVar as Benign. ClinVar VariationId is 1246461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

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.58-48A>T	intron	N/A	NP_002875.1	P62834
RAP1A	NM_001010935.3		c.58-48A>T	intron	N/A	NP_001010935.1	P62834
RAP1A	NM_001291896.3		c.58-48A>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.58-48A>T	intron	N/A	ENSP00000358723.3	P62834
RAP1A	ENST00000356415.5	TSL:1	c.58-48A>T	intron	N/A	ENSP00000348786.1	P62834
RAP1A	ENST00000687939.1		c.58-48A>T	intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47286

AN:

151864

Hom.:

7687

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.339

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.467

Gnomad SAS

AF:

0.390

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.353

Gnomad OTH

AF:

0.335

GnomAD2 exomes

AF:

0.346

AC:

57276

AN:

165440

AF XY:

0.353

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.341

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.463

Gnomad FIN exome

AF:

0.293

Gnomad NFE exome

AF:

0.355

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.353

AC:

432667

AN:

1226372

Hom.:

77742

Cov.:

AF XY:

0.354

AC XY:

218433

AN XY:

616178

show subpopulations

African (AFR)

AF:

0.193

AC:

4787

AN:

24762

American (AMR)

AF:

0.343

AC:

8837

AN:

25734

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

8393

AN:

22952

East Asian (EAS)

AF:

0.448

AC:

15190

AN:

33890

South Asian (SAS)

AF:

0.375

AC:

25545

AN:

68208

European-Finnish (FIN)

AF:

0.287

AC:

14657

AN:

51006

Middle Eastern (MID)

AF:

0.416

AC:

1570

AN:

3774

European-Non Finnish (NFE)

AF:

0.355

AC:

335493

AN:

944778

Other (OTH)

AF:

0.355

AC:

18195

AN:

51268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

12959

25918

38876

51835

64794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10350

20700

31050

41400

51750

<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

AF:

0.311

AC:

47284

AN:

151982

Hom.:

7686

Cov.:

AF XY:

0.313

AC XY:

23260

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.196

AC:

8145

AN:

41474

American (AMR)

AF:

0.353

AC:

5395

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

1261

AN:

3470

East Asian (EAS)

AF:

0.467

AC:

2412

AN:

5162

South Asian (SAS)

AF:

0.389

AC:

1878

AN:

4826

European-Finnish (FIN)

AF:

0.290

AC:

3054

AN:

10520

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.353

AC:

24010

AN:

67948

Other (OTH)

AF:

0.332

AC:

699

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1640

3280

4920

6560

8200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.329

Hom.:

1566

Bravo

AF:

0.312

Asia WGS

AF:

0.373

AC:

1289

AN:

3460

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.0

(source)

DANN

Benign

0.46

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over