rs28935498

Positions:

chrX-54470182-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The ENST00000375135.4(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

Genomes: 𝑓 0.00037 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00080 ( 1 hom. 282 hem. )

Consequence

FGD1
ENST00000375135.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:8

Conservation

PhyloP100: 2.02

Variant links:

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]

FGD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGD1. . Gene score misZ 3.5183 (greater than the threshold 3.09). GenCC has associacion of gene with Aarskog-Scott syndrome, X-linked.

BP4

Computational evidence support a benign effect (MetaRNN=0.07815245).

BP6

Variant X-54470182-G-A is Benign according to our data. Variant chrX-54470182-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10828.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}. Variant chrX-54470182-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000365 (41/112206) while in subpopulation NFE AF= 0.000621 (33/53155). AF 95% confidence interval is 0.000454. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD1	NM_004463.3 linkuse as main transcript	c.935C>T	p.Pro312Leu	missense_variant	4/18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 linkuse as main transcript	c.935C>T	p.Pro312Leu	missense_variant	4/18	1	NM_004463.3	ENSP00000364277	P1

Frequencies

GnomAD3 genomes

AF:

0.000357

AC:

AN:

112151

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

34305

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000942

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000621

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.000314

AC:

AN:

175104

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

60954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000697

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.000803

AC:

880

AN:

1095919

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

282

AN XY:

361441

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000496

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.000631

GnomAD4 genome

AF:

0.000365

AC:

AN:

112206

Hom.:

Cov.:

AF XY:

0.000320

AC XY:

AN XY:

34370

show subpopulations

Gnomad4 AFR

AF:

0.000129

Gnomad4 AMR

AF:

0.0000940

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000621

Gnomad4 OTH

AF:

0.00130

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000397

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	FGD1: PP2, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2016	- -

Aarskog syndrome

Pathogenic:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -

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, no assertion criteria provided

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.74

M_CAP

Benign

0.057

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.39

Sift

Benign

0.055

Sift4G

Uncertain

0.057

Polyphen

0.0

Vest4

0.12

MVP

0.94

MPC

0.31

ClinPred

0.053

GERP RS

3.8

Varity_R

0.20

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over