chrX-54470714-TG-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004463.3(FGD1):βc.527delCβ(p.Pro176HisfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0 ( 0 hom., 0 hem., cov: 19)
Exomes π: 0.0011 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
FGD1
NM_004463.3 frameshift
NM_004463.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.452
Genes affected
FGD1 (HGNC:3663): (FYVE, RhoGEF and PH domain containing 1) This gene encodes a protein that contains Dbl (DH) and pleckstrin (PH) homology domains and is similar to the Rho family of small GTP-binding proteins. The encoded protein specifically binds to the Rho family GTPase Cdc42Hs and can stimulate the GDP-GTP exchange of the isoprenylated form of Cdc42Hs. It also stimulates the mitogen activated protein kinase cascade leading to c-Jun kinase SAPK/JNK1 activation. Defects in this gene are the cause of the faciogenital dysplasia in Aarskog-Scott syndrome and a syndromatic form of X-linked cognitive disability. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant X-54470714-TG-T is Pathogenic according to our data. Variant chrX-54470714-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54470714-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGD1 | NM_004463.3 | c.527delC | p.Pro176HisfsTer39 | frameshift_variant | Exon 3 of 18 | ENST00000375135.4 | NP_004454.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 7890Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0AN XY: 1370 FAILED QC
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GnomAD4 exome AF: 0.00110 AC: 197AN: 178387Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0AN XY: 36891
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aarskog syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 12, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 3 of 18). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar, Orrico, A. et al. (2010)). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Dec 19, 2014 | Our laboratory reported dual molecular diagnoses in PAFAH1B1 (NM_000430.3, c.484G>A) and FGD1 (NM_004463.2, c.527delC) in this individual with reported features of intrauterine growth restriction, delayed motor milestones, delayed speech, autism, intellectual disability, hearing loss, hypotonia, seizure disorder, ataxia, dysmorphic features, short stature, microcephaly, failure to thrive, eye anomalies, skeletal abnormalities and scoliosis, and structural brain anomalies. The PAFAH1B1 variant has been reported in one patient with a mild LIS1 phenotype [PMID: 11115846, 12885786]. The FGD1 variant is predicted to cause a frameshift and is categorized as deleterious by ACMGG guidelines [PMID: 18414213]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Aug 15, 2023 | This sequence variant is a single nucleotide deletion in exon 3 of 18 of the FGD1 gene that results in an early termition codon 39 amino acids downstream of the frameshift at codon 176. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of FGD1 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 374329) that has been observed in the literature in an individual with phenotypes consistent with Aarskog-Scott syndrome (PMID: 27959697). This variant is absent from the gnomAD population database (0/~131000 alleles). Haploinsufficiency in FGD1 is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Apr 27, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Apr 04, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27959697, 34189097) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2024 | This sequence change creates a premature translational stop signal (p.Pro176Hisfs*39) in the FGD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FGD1 are known to be pathogenic (PMID: 21739585, 23211637, 25046119, 26029706). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with FGD1-related conditions (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374329). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 09, 2017 | The c.527delC pathogenic mutation, located in coding exon 3 of the FGD1 gene, results from a deletion of one nucleotide at nucleotide position 527, causing a translational frameshift with a predicted alternate stop codon (p.P176Hfs*39). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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SpliceAI score (max)
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