rs150501049

Variant summary

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

The NM_016340.6(RAPGEF6):​c.4112G>C​(p.Ser1371Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1371N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

RAPGEF6
NM_016340.6 missense

Scores

5
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.69
Variant links:
Genes affected
RAPGEF6 (HGNC:20655): (Rap guanine nucleotide exchange factor 6) Enables several functions, including GTP-dependent protein binding activity; guanyl-nucleotide exchange factor activity; and phosphatidic acid binding activity. Involved in microvillus assembly; positive regulation of GTPase activity; and protein localization to plasma membrane. Located in several cellular components, including apical plasma membrane; centrosome; and endocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

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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=0.16087046).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAPGEF6NM_016340.6 linkc.4112G>C p.Ser1371Thr missense_variant Exon 26 of 28 ENST00000509018.6 NP_057424.3 Q8TEU7-1
RAPGEF6NM_001164386.2 linkc.4136G>C p.Ser1379Thr missense_variant Exon 27 of 29 NP_001157858.1 Q8TEU7-4B2RTU6
RAPGEF6NM_001164387.2 linkc.4151G>C p.Ser1384Thr missense_variant Exon 28 of 29 NP_001157859.1 Q8TEU7-3
RAPGEF6NM_001164388.2 linkc.4136G>C p.Ser1379Thr missense_variant Exon 27 of 28 NP_001157860.1 Q8TEU7-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAPGEF6ENST00000509018.6 linkc.4112G>C p.Ser1371Thr missense_variant Exon 26 of 28 1 NM_016340.6 ENSP00000421684.1 Q8TEU7-1
ENSG00000273217ENST00000514667.1 linkc.4262G>C p.Ser1421Thr missense_variant Exon 27 of 29 2 ENSP00000426948.1 E9PCH4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461888
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.092
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.16
T;.;.;.;.
Eigen
Benign
-0.051
Eigen_PC
Benign
0.073
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.93
D;D;D;D;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.16
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M;.;.;.;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.68
N;.;N;.;N
REVEL
Benign
0.089
Sift
Benign
0.080
T;.;T;.;T
Sift4G
Benign
0.22
T;T;T;T;T
Polyphen
0.0090
B;B;.;.;.
Vest4
0.31
MutPred
0.23
.;.;.;.;Gain of catalytic residue at S1421 (P = 0.0112);
MVP
0.48
MPC
0.18, 0.17
ClinPred
0.78
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-130766905; API