dbSNP rs494453: RAP1A:c.-28+29566T>C (chr1-111649500-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002884.4(RAP1A):c.-28+29566T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 299,118 control chromosomes in the GnomAD database, including 24,769 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 0.41 ( 12784 hom., cov: 32)

Exomes 𝑓: 0.40 ( 11985 hom. )

Consequence

RAP1A
NM_002884.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.155

Publications

32 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:

KRT18P57 (HGNC:48884): (keratin 18 pseudogene 57)

KRT18P57 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=-0.97).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAP1A	NM_002884.4 link	c.-28+29566T>C		intron_variant	Intron 1 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.-28+29566T>C		intron_variant	Intron 1 of 7	1	NM_002884.4	ENSP00000358723.3		P62834

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61981

AN:

151918

Hom.:

12766

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.410

Gnomad EAS

AF:

0.440

Gnomad SAS

AF:

0.375

Gnomad FIN

AF:

0.474

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.388

GnomAD4 exome

AF:

0.399

AC:

58681

AN:

147082

Hom.:

11985

Cov.:

AF XY:

0.394

AC XY:

32541

AN XY:

82560

show subpopulations

African (AFR)

AF:

0.471

AC:

1810

AN:

3844

American (AMR)

AF:

0.526

AC:

7339

AN:

13960

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

1126

AN:

2782

East Asian (EAS)

AF:

0.429

AC:

2984

AN:

6958

South Asian (SAS)

AF:

0.396

AC:

8434

AN:

21284

European-Finnish (FIN)

AF:

0.465

AC:

4029

AN:

8668

Middle Eastern (MID)

AF:

0.348

AC:

135

AN:

388

European-Non Finnish (NFE)

AF:

0.366

AC:

30132

AN:

82304

Other (OTH)

AF:

0.390

AC:

2692

AN:

6894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1733

3466

5199

6932

8665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.408

AC:

62037

AN:

152036

Hom.:

12784

Cov.:

AF XY:

0.411

AC XY:

30510

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.461

AC:

19130

AN:

41476

American (AMR)

AF:

0.427

AC:

6520

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.410

AC:

1423

AN:

3468

East Asian (EAS)

AF:

0.439

AC:

2266

AN:

5160

South Asian (SAS)

AF:

0.376

AC:

1810

AN:

4812

European-Finnish (FIN)

AF:

0.474

AC:

5001

AN:

10552

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.363

AC:

24665

AN:

67962

Other (OTH)

AF:

0.391

AC:

828

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1901

3802

5702

7603

9504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.334

Hom.:

4160

Bravo

AF:

0.409

Asia WGS

AF:

0.459

AC:

1597

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

7.2

(source)

DANN

Benign

0.38

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over