8-67343250-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_006421.5(ARFGEF1):​c.38C>T​(p.Thr13Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,666 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: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARFGEF1
NM_006421.5 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
ARFGEF1 (HGNC:15772): (ADP ribosylation factor guanine nucleotide exchange factor 1) 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. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Aug 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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), ARFGEF1. . Gene score misZ 5.3687 (greater than the threshold 3.09). Trascript score misZ 6.9454 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, schizophrenia.
BP4
Computational evidence support a benign effect (MetaRNN=0.33300632).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARFGEF1NM_006421.5 linkuse as main transcriptc.38C>T p.Thr13Ile missense_variant 1/39 ENST00000262215.8 NP_006412.2 Q9Y6D6A0A024R7X0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARFGEF1ENST00000262215.8 linkuse as main transcriptc.38C>T p.Thr13Ile missense_variant 1/391 NM_006421.5 ENSP00000262215.3 Q9Y6D6
ARFGEF1ENST00000519436.1 linkuse as main transcriptc.38C>T p.Thr13Ile missense_variant 2/53 ENSP00000429002.1 E5RJN9

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461666
Hom.:
0
Cov.:
48
AF XY:
0.00
AC XY:
0
AN XY:
727148
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 07, 2023The c.38C>T (p.T13I) alteration is located in exon 1 (coding exon 1) of the ARFGEF1 gene. This alteration results from a C to T substitution at nucleotide position 38, causing the threonine (T) at amino acid position 13 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. 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
Uncertain
0.38
BayesDel_addAF
Uncertain
0.026
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.12
T;.
Eigen
Benign
-0.046
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.33
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.28
N;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-0.92
N;N
REVEL
Benign
0.22
Sift
Benign
0.31
T;T
Sift4G
Benign
0.26
T;T
Polyphen
0.021
B;.
Vest4
0.55
MutPred
0.33
Loss of disorder (P = 0.0385);Loss of disorder (P = 0.0385);
MVP
0.54
MPC
0.39
ClinPred
0.81
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.55
gMVP
0.39

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: chr8-68255485; API