rs201206379
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP7BS1_Supporting
The NM_006420.3(ARFGEF2):c.4332G>A(p.Ala1444=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,956 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: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
ARFGEF2
NM_006420.3 synonymous
NM_006420.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.384
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 Likely_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP7
?
Synonymous conserved (PhyloP=-0.384 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000788 (12/152272) while in subpopulation EAS AF= 0.000964 (5/5186). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARFGEF2 | NM_006420.3 | c.4332G>A | p.Ala1444= | synonymous_variant | 32/39 | ENST00000371917.5 | |
ARFGEF2 | NM_001410846.1 | c.4329G>A | p.Ala1443= | synonymous_variant | 32/39 | ||
ARFGEF2 | XM_047439832.1 | c.3768G>A | p.Ala1256= | synonymous_variant | 30/37 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARFGEF2 | ENST00000371917.5 | c.4332G>A | p.Ala1444= | synonymous_variant | 32/39 | 1 | NM_006420.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251228Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135810
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727140
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GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74428
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 17, 2014 | - - |
Periventricular heterotopia with microcephaly, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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