rs28935498
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_004463.3(FGD1):c.935C>T(p.Pro312Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,208,125 control chromosomes in the GnomAD database, including 1 homozygotes. There are 293 hemizygotes in GnomAD. 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_004463.3 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGD1 | NM_004463.3 | c.935C>T | p.Pro312Leu | missense_variant | 4/18 | ENST00000375135.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGD1 | ENST00000375135.4 | c.935C>T | p.Pro312Leu | missense_variant | 4/18 | 1 | NM_004463.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000357 AC: 40AN: 112151Hom.: 0 Cov.: 23 AF XY: 0.000292 AC XY: 10AN XY: 34305
GnomAD3 exomes AF: 0.000314 AC: 55AN: 175104Hom.: 0 AF XY: 0.000295 AC XY: 18AN XY: 60954
GnomAD4 exome AF: 0.000803 AC: 880AN: 1095919Hom.: 1 Cov.: 33 AF XY: 0.000780 AC XY: 282AN XY: 361441
GnomAD4 genome ? AF: 0.000365 AC: 41AN: 112206Hom.: 0 Cov.: 23 AF XY: 0.000320 AC XY: 11AN XY: 34370
ClinVar
Submissions by phenotype
not provided Benign:5
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 19, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | FGD1: PP2, BS2 - |
Aarskog syndrome Pathogenic:1Benign:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2002 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2015 | The p.P312L variant (also known as c.935C>T), located in coding exon 4 of the FGD1 gene, results from a C to T substitution at nucleotide position 935. The proline at codon 312 is replaced by leucine, an amino acid with similar properties. This variant was observed to co-segregate with disease in three affected male full siblings with intellectual disability, severe speech delays, macrocephaly, antitragus, open mouth, high arched palate, and short stature; one affected sibling was diagnosed with shawl scrotum and cryptorchidism. The alteration was observed to be maternally inherited and was absent in two healthy maternal uncles (providing a LOD score of 0.9). This alteration was absent out of 300 X chromosomes from controls, 204 males and 48 females (Lebel, RR et al. Clin Genet 2002;61:139-145). This variant was previously reported in the SNPDatabase as rs28935498. Based on data from the 1000 Genomes Project, the T allele has an overall frequency of approximately 0% (0/503) total male alleles studied. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.08% (2/2440) total male alleles studied and 0.11% (2/1870) European American male alleles. This alteration occurs within the proline rich domain (PRD) at the N-terminus of the protein which is speculated to play a crucial role in the temporally and spatially regulated activation of the FGD1 protein (Genot, E et al. J Cell Sci 2012;125:3265-70, Oshima, T et al. Biol Pharm Bull 2011;34:54-60). Utilization of in silico analysis tools for secondary structure effect by Lebel et al 2002, predicted that a beta-turn in the protein structure is eliminated by this substitution and results in a two-fold increased lengthening of this coil region. Authors speculate that this beta-turn may serve as a linker between two domains of the protein, which may affect the orientations of an SH3 (Src homology 3) binding domain and the first structural conserved region. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since clinical data on this variant is limited at this time, its clinical significance is unclear. - |
FGD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 21, 2023 | 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). - |
Intellectual disability Benign:1
Likely benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at