rs28935498

chrX-54470182-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

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:
  • Genomes: 𝑓 0.00037 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00080 (1 hom. 282 hem.)
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8
• Conservation: PhyloP100: 2.02

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FGD1
• 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=3}. 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. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 10 XL gene

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: 40 AN: 112151 Hom.: 0 Cov.: 23 AF XY: 0.000292 AC XY: 10 AN XY: 34305

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: 55 AN: 175104 Hom.: 0 AF XY: 0.000295 AC XY: 18 AN XY: 60954

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.: 1 Cov.: 33 AF XY: 0.000780 AC XY: 282 AN XY: 361441

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: 41 AN: 112206 Hom.: 0 Cov.: 23 AF XY: 0.000320 AC XY: 11 AN XY: 34370

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.: 2

Bravo AF: 0.000397

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00104 AC: 7

ExAC AF: 0.000338 AC: 41

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	FGD1: PP2, BS2 -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	- -

Aarskog syndrome Pathogenic:1 Benign: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, 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.99	A
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.39
Sift	Benign	0.055	T
Sift4G	Uncertain	0.057	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.94
MPC		0.31
ClinPred		0.053	T
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

Other links and lift over

dbSNP: rs28935498; hg19: chrX-54496615;