8-67343214-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The ENST00000262215.8(ARFGEF1):​c.74T>C​(p.Val25Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

ARFGEF1
ENST00000262215.8 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.79
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 1 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=0.23942158).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARFGEF1NM_006421.5 linkuse as main transcriptc.74T>C p.Val25Ala missense_variant 1/39 ENST00000262215.8 NP_006412.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARFGEF1ENST00000262215.8 linkuse as main transcriptc.74T>C p.Val25Ala missense_variant 1/391 NM_006421.5 ENSP00000262215 P1
ARFGEF1ENST00000519436.1 linkuse as main transcriptc.74T>C p.Val25Ala missense_variant 2/53 ENSP00000429002

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
48
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 01, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Benign
-0.35
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.44
T;.
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.78
T;T
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.24
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.55
N;.
MutationTaster
Benign
0.99
D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-2.4
N;D
REVEL
Benign
0.24
Sift
Benign
0.36
T;T
Sift4G
Benign
0.29
T;T
Polyphen
0.0040
B;.
Vest4
0.57
MutPred
0.35
Loss of methylation at K26 (P = 0.0365);Loss of methylation at K26 (P = 0.0365);
MVP
0.61
MPC
0.43
ClinPred
0.65
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.20
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr8-68255449; API