1-111704349-A-G
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_002884.4(RAP1A):āc.331A>Gā(p.Met111Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,613,522 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 (ā ).
Frequency
Genomes: š 0.000072 ( 0 hom., cov: 32)
Exomes š: 0.000068 ( 0 hom. )
Consequence
RAP1A
NM_002884.4 missense
NM_002884.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 8.95
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.24209297).
BS2
High AC in GnomAd4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAP1A | NM_002884.4 | c.331A>G | p.Met111Val | missense_variant | 6/8 | ENST00000369709.4 | NP_002875.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAP1A | ENST00000369709.4 | c.331A>G | p.Met111Val | missense_variant | 6/8 | 1 | NM_002884.4 | ENSP00000358723 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000724 AC: 11AN: 152012Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000837 AC: 21AN: 250958Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135612
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GnomAD4 exome AF: 0.0000684 AC: 100AN: 1461392Hom.: 0 Cov.: 30 AF XY: 0.0000715 AC XY: 52AN XY: 726982
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GnomAD4 genome AF: 0.0000723 AC: 11AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74358
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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 | Jun 10, 2022 | The c.331A>G (p.M111V) alteration is located in exon 7 (coding exon 5) of the RAP1A gene. This alteration results from a A to G substitution at nucleotide position 331, causing the methionine (M) at amino acid position 111 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;N
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;.;B
Vest4
MVP
MPC
1.7
ClinPred
T
GERP RS
Varity_R
gMVP
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