1-21599538-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002885.4(RAP1GAP):c.1732G>A(p.Val578Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000398 in 1,609,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
RAP1GAP
NM_002885.4 missense
NM_002885.4 missense
Scores
1
7
5
Clinical Significance
Conservation
PhyloP100: 3.60
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]
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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=0.089049965).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAP1GAP | NM_002885.4 | c.1732G>A | p.Val578Met | missense_variant | 21/25 | ENST00000374765.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAP1GAP | ENST00000374765.9 | c.1732G>A | p.Val578Met | missense_variant | 21/25 | 1 | NM_002885.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000726 AC: 18AN: 247828Hom.: 0 AF XY: 0.0000744 AC XY: 10AN XY: 134324
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GnomAD4 exome AF: 0.0000343 AC: 50AN: 1457488Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23AN XY: 725280
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GnomAD4 genome AF: 0.0000919 AC: 14AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74472
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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 | Feb 17, 2024 | The c.1924G>A (p.V642M) alteration is located in exon 21 (coding exon 21) of the RAP1GAP gene. This alteration results from a G to A substitution at nucleotide position 1924, causing the valine (V) at amino acid position 642 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
Sift4G
Benign
T
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at