Genetic Variant RAPGEF5:c.997-8884A>G (chr7-22202917-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_012294.5(RAPGEF5):c.997-8884A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 364,202 control chromosomes in the GnomAD database, including 48,051 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 0.54 ( 21808 hom., cov: 32)

Exomes 𝑓: 0.49 ( 26243 hom. )

Consequence

RAPGEF5
NM_012294.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.87

Publications

4 publications found

Variant links:

Genes affected

RAPGEF5 (HGNC:16862): (Rap guanine nucleotide exchange factor 5) Members of the RAS (see HRAS; MIM 190020) subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF5, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation (Rebhun et al., 2000 [PubMed 10934204]).[supplied by OMIM, Mar 2008]

RAPGEF5 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=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF5	NM_012294.5 link	c.997-8884A>G		intron_variant	Intron 9 of 25	ENST00000665637.1	NP_036426.4	Q92565A8MQ07Q5JPD2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF5	ENST00000665637.1 link	c.997-8884A>G		intron_variant	Intron 9 of 25		NM_012294.5	ENSP00000499535.1		A0A590UJR0

Frequencies

GnomAD3 genomes

AF:

0.536

AC:

81351

AN:

151870

Hom.:

21788

Cov.:

show subpopulations

Gnomad AFR

AF:

0.525

Gnomad AMI

AF:

0.592

Gnomad AMR

AF:

0.462

Gnomad ASJ

AF:

0.477

Gnomad EAS

AF:

0.573

Gnomad SAS

AF:

0.511

Gnomad FIN

AF:

0.539

Gnomad MID

AF:

0.478

Gnomad NFE

AF:

0.560

Gnomad OTH

AF:

0.507

GnomAD2 exomes

AF:

0.467

AC:

39993

AN:

85558

AF XY:

0.476

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.346

Gnomad ASJ exome

AF:

0.421

Gnomad EAS exome

AF:

0.507

Gnomad FIN exome

AF:

0.482

Gnomad NFE exome

AF:

0.515

Gnomad OTH exome

AF:

0.443

GnomAD4 exome

AF:

0.491

AC:

104202

AN:

212214

Hom.:

26243

Cov.:

AF XY:

0.494

AC XY:

60967

AN XY:

123422

show subpopulations

African (AFR)

AF:

0.463

AC:

2508

AN:

5422

American (AMR)

AF:

0.353

AC:

5263

AN:

14926

Ashkenazi Jewish (ASJ)

AF:

0.426

AC:

2993

AN:

7032

East Asian (EAS)

AF:

0.509

AC:

3225

AN:

6332

South Asian (SAS)

AF:

0.474

AC:

20616

AN:

43508

European-Finnish (FIN)

AF:

0.504

AC:

4997

AN:

9914

Middle Eastern (MID)

AF:

0.348

AC:

846

AN:

2432

European-Non Finnish (NFE)

AF:

0.522

AC:

58896

AN:

112736

Other (OTH)

AF:

0.490

AC:

4858

AN:

9912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

1817

3633

5450

7266

9083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.536

AC:

81403

AN:

151988

Hom.:

21808

Cov.:

AF XY:

0.534

AC XY:

39668

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.525

AC:

21736

AN:

41424

American (AMR)

AF:

0.463

AC:

7071

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.477

AC:

1654

AN:

3470

East Asian (EAS)

AF:

0.572

AC:

2958

AN:

5170

South Asian (SAS)

AF:

0.511

AC:

2463

AN:

4816

European-Finnish (FIN)

AF:

0.539

AC:

5691

AN:

10550

Middle Eastern (MID)

AF:

0.463

AC:

136

AN:

294

European-Non Finnish (NFE)

AF:

0.560

AC:

38079

AN:

67954

Other (OTH)

AF:

0.508

AC:

1075

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1989

3978

5966

7955

9944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.548

Hom.:

98070

Bravo

AF:

0.530

Asia WGS

AF:

0.535

AC:

1861

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.25

(source)

DANN

Benign

0.73

PhyloP100

-1.9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over