12-32610778-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001370298.3(FGD4):āc.1546T>Gā(p.Ser516Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,460,642 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 (ā ). Synonymous variant affecting the same amino acid position (i.e. S516S) has been classified as Likely benign.
Frequency
Consequence
NM_001370298.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGD4 | NM_001370298.3 | c.1546T>G | p.Ser516Ala | missense_variant, splice_region_variant | 9/17 | ENST00000534526.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGD4 | ENST00000534526.7 | c.1546T>G | p.Ser516Ala | missense_variant, splice_region_variant | 9/17 | 5 | NM_001370298.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250796Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135634
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460642Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726704
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2017 | This sequence change replaces serine with alanine at codon 379 of the FGD4 protein (p.Ser379Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FGD4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at