Variant 1-21598035-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002885.4(RAP1GAP):c.1909G>A(p.Gly637Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 1,543,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

RAP1GAP
NM_002885.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.210

Variant links:

Genes affected

RAP1GAP (HGNC:9858): (RAP1 GTPase activating protein) This gene encodes a type of GTPase-activating-protein (GAP) that down-regulates the activity of the ras-related RAP1 protein. RAP1 acts as a molecular switch by cycling between an inactive GDP-bound form and an active GTP-bound form. The product of this gene, RAP1GAP, promotes the hydrolysis of bound GTP and hence returns RAP1 to the inactive state whereas other proteins, guanine nucleotide exchange factors (GEFs), act as RAP1 activators by facilitating the conversion of RAP1 from the GDP- to the GTP-bound form. In general, ras subfamily proteins, such as RAP1, play key roles in receptor-linked signaling pathways that control cell growth and differentiation. RAP1 plays a role in diverse processes such as cell proliferation, adhesion, differentiation, and embryogenesis. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Aug 2011]

RAP1GAP links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13076296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1GAP	NM_002885.4 linkuse as main transcript	c.1909G>A	p.Gly637Ser	missense_variant	23/25	ENST00000374765.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1GAP	ENST00000374765.9 linkuse as main transcript	c.1909G>A	p.Gly637Ser	missense_variant	23/25	1	NM_002885.4	A1	P47736-1

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.000482

GnomAD4 exome

AF:

0.00000790

AC:

AN:

1393274

Hom.:

Cov.:

AF XY:

0.00000724

AC XY:

AN XY:

690258

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000839

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150634

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73534

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.000482

Bravo

AF:

0.0000113

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.2101G>A (p.G701S) alteration is located in exon 23 (coding exon 23) of the RAP1GAP gene. This alteration results from a G to A substitution at nucleotide position 2101, causing the glycine (G) at amino acid position 701 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0078

.;T;T;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.2

.;.;L;.;.

MutationTaster

Benign

0.96

N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

0.080

.;N;N;N;.

REVEL

Uncertain

0.35

Sift

Benign

0.26

.;T;T;T;.

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

0.0060, 0.0010

.;.;B;B;.

Vest4

0.23

MutPred

0.091

.;.;Gain of glycosylation at G637 (P = 0.0053);.;.;

MVP

0.30

ClinPred

0.28

GERP RS

-1.3

Varity_R

0.094

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over