20-48998348-G-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_006420.3(ARFGEF2):c.3275G>T(p.Arg1092Leu) variant causes a missense change. 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ARFGEF2
NM_006420.3 missense
NM_006420.3 missense
Scores
6
10
3
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 6.89
Genes affected
ARFGEF2 (HGNC:15853): (ADP ribosylation factor guanine nucleotide exchange factor 2) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ARFGEF2. . Gene score misZ 2.5971 (greater than the threshold 3.09). Trascript score misZ 4.3519 (greater than threshold 3.09). GenCC has associacion of gene with periventricular nodular heterotopia, periventricular heterotopia with microcephaly, autosomal recessive.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.851
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARFGEF2 | NM_006420.3 | c.3275G>T | p.Arg1092Leu | missense_variant | 25/39 | ENST00000371917.5 | NP_006411.2 | |
ARFGEF2 | NM_001410846.1 | c.3272G>T | p.Arg1091Leu | missense_variant | 25/39 | NP_001397775.1 | ||
ARFGEF2 | XM_047439832.1 | c.2711G>T | p.Arg904Leu | missense_variant | 23/37 | XP_047295788.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARFGEF2 | ENST00000371917.5 | c.3275G>T | p.Arg1092Leu | missense_variant | 25/39 | 1 | NM_006420.3 | ENSP00000360985.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 exome
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1
AN:
1461888
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Cov.:
34
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0
AN XY:
727242
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
TwinsUK
AF:
AC:
0
ALSPAC
AF:
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1
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of MoRF binding (P = 0.0779);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at