chr12-32619725-C-A
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2
The NM_001370298.3(FGD4):c.1777C>A(p.Pro593Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,932 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001370298.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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FGD4 | NM_001370298.3 | c.1777C>A | p.Pro593Thr | missense_variant | Exon 11 of 17 | ENST00000534526.7 | NP_001357227.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00155 AC: 235AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00140 AC: 351AN: 251470Hom.: 1 AF XY: 0.00138 AC XY: 188AN XY: 135906
GnomAD4 exome AF: 0.00205 AC: 2995AN: 1461888Hom.: 8 Cov.: 32 AF XY: 0.00200 AC XY: 1458AN XY: 727246
GnomAD4 genome AF: 0.00155 AC: 235AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105AN XY: 74242
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
FGD4: PP3, BS1 -
See Variant Classification Assertion Criteria. -
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Charcot-Marie-Tooth disease type 4H Uncertain:2
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. -
The FGD4 c.1366C>A; p.Pro456Thr variant (rs138160928), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 188187). This variant is found in the non-Finnish European population with an overall allele frequency of 0.27% (344/129172 alleles, including one homozygote) in the Genome Aggregation Database. The proline at codon 456 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.717). However, due to limited information, the clinical significance of the p.Pro456Thr variant is uncertain at this time. -
not specified Uncertain:1Benign:1
Variant summary: FGD4 c.1366C>A (p.Pro456Thr) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251470 control chromosomes, predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. c.1366C>A has been reported in the literature in individuals affected with inherited peripheral neuropaty without strong evidence for causality (Atoniadi_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Type 4H. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is also known as c.177C>A (p.P593T). The following publication have been ascertained in the context of this evaluation (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 188187). Based on the evidence outlined above, the variant was classified as likely benign. -
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Charcot-Marie-Tooth disease Benign:1
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
FGD4-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Charcot-Marie-Tooth disease type 4 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at