rs1557191567
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004463.3(FGD1):c.277_278insT(p.Tyr93LeufsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
FGD1
NM_004463.3 frameshift
NM_004463.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.75
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-54495155-T-TA is Pathogenic according to our data. Variant chrX-54495155-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGD1 | NM_004463.3 | c.277_278insT | p.Tyr93LeufsTer21 | frameshift_variant | 1/18 | ENST00000375135.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGD1 | ENST00000375135.4 | c.277_278insT | p.Tyr93LeufsTer21 | frameshift_variant | 1/18 | 1 | NM_004463.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aarskog syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 16, 2022 | The de novo hemizygous one nucleotide duplication [c.277dup, p.(Tyr93LeufsTer21)] identified in exon 1 (of 18) of FGD1 has not been reported in affected individuals in the literature, though it has been deposited in the ClinVar database as Likely Pathogenic by another genetic testing laboratory [Variation ID: 547364]. This c.277dup alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is absent from population databases (gnomADv2, gnomADv3, TOPMed Freeze 8) suggesting it is not a common benign variant in populations represented in those databases. Based on the available evidence, the de novo hemizygous one nucleotide duplication [c.277dup, p.(Tyr93LeufsTer21)] identified in the FGD1 gene is reported as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
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Calibrated prediction
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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