X-54471400-C-T
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_004463.3(FGD1):c.395G>A(p.Arg132Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00196 in 1,209,766 control chromosomes in the GnomAD database, including 1 homozygotes. There are 720 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., 43 hem., cov: 23)
Exomes 𝑓: 0.0020 ( 1 hom. 677 hem. )
Consequence
FGD1
NM_004463.3 missense
NM_004463.3 missense
Scores
1
2
14
Clinical Significance
Conservation
PhyloP100: 4.86
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 Benign. Variant got -19 ACMG points.
PP2
Missense variant where missense usually causes diseases, FGD1
BP4
Computational evidence support a benign effect (MetaRNN=0.0061568916).
BP6
Variant X-54471400-C-T is Benign according to our data. Variant chrX-54471400-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54471400-C-T is described in Lovd as [Likely_benign]. Variant chrX-54471400-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00124 (140/112605) while in subpopulation NFE AF= 0.00206 (110/53301). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 43 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGD1 | NM_004463.3 | c.395G>A | p.Arg132Gln | missense_variant | 2/18 | ENST00000375135.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGD1 | ENST00000375135.4 | c.395G>A | p.Arg132Gln | missense_variant | 2/18 | 1 | NM_004463.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00124 AC: 140AN: 112555Hom.: 0 Cov.: 23 AF XY: 0.00124 AC XY: 43AN XY: 34709
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GnomAD3 exomes AF: 0.00132 AC: 242AN: 183402Hom.: 0 AF XY: 0.00124 AC XY: 84AN XY: 67840
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GnomAD4 exome AF: 0.00204 AC: 2236AN: 1097161Hom.: 1 Cov.: 31 AF XY: 0.00187 AC XY: 677AN XY: 362863
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GnomAD4 genome AF: 0.00124 AC: 140AN: 112605Hom.: 0 Cov.: 23 AF XY: 0.00124 AC XY: 43AN XY: 34769
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 14, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Aarskog syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 11, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 29, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2016 | This alteration is classified as 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. - |
FGD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 07, 2019 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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