Variant X-54470714-TGG-TGGG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting

The ENST00000375135.4(FGD1):c.527_528insC(p.Leu177ThrfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P176P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.0026 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

FGD1
ENST00000375135.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 0.452

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant X-54470714-T-TG is Pathogenic according to our data. Variant chrX-54470714-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 196389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00261 (462/177336) while in subpopulation NFE AF= 0.00316 (370/117032). AF 95% confidence interval is 0.0029. There are 0 homozygotes in gnomad4_exome. There are 0 alleles in male gnomad4_exome subpopulation. Median coverage is 16. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD1	NM_004463.3 linkuse as main transcript	c.527_528insC	p.Leu177ThrfsTer40	frameshift_variant	3/18	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.527_528insC	p.Leu177ThrfsTer40	frameshift_variant	3/18	1	NM_004463.3	ENSP00000364277	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

7879

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

1365

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00261

AC:

462

AN:

177336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

36504

show subpopulations

Gnomad4 AFR exome

AF:

0.00285

Gnomad4 AMR exome

AF:

0.00142

Gnomad4 ASJ exome

AF:

0.00106

Gnomad4 EAS exome

AF:

0.00129

Gnomad4 SAS exome

AF:

0.000919

Gnomad4 FIN exome

AF:

0.00127

Gnomad4 NFE exome

AF:

0.00316

Gnomad4 OTH exome

AF:

0.00227

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

7912

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

1376

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000994

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 196389). This premature translational stop signal has been observed in individual(s) with FGD1-related conditions (PMID: 14560308, 29276006). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Leu177Thrfs*40) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 26, 2021	PVS1, PM2, PS4_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Reported in multiple individuals with clinical features of Aarskog-Scott syndrome from two unrelated families (Orrico et al., 2004); 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14560308) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Aarskog syndrome

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jun 01, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 13, 2024	The hemizygous p.Leu177ThrfsTer40 variant in FGD1 was identified by our study in one individual with short stature and congenital fibrosis of the extraocular muscles, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Leu177ThrfsTer40 variant in FGD1 has been previously reported in 4 unrelated individuals with Aarskog-Scott syndrome (PMID: 14560308, PMID: 29276006, PMID: 35388608, ClinVar Accession SCV002058304.1) and segregated with disease in 3 affected male relatives from one family, 2 of whom were monozygotic twins (PMID: 14560308). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (Variation ID: 196389) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 177 and leads to a premature termination codon 40 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the FGD1 gene is an established disease mechanism in X-linked recessive Aarskog-Scott syndrome. In summary, this variant meets criteria to be classified as pathogenic for X-linked recessive Aarskog-Scott syndrome. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PP1 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000196389, PMID:14560308). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002315, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

FGD1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2023

The FGD1 c.527dupC variant is predicted to result in a frameshift and premature protein termination (p.Leu177Thrfs*40). This variant was reported in multiple individuals with Aarskog-Scott syndrome (referred to as 528insC in Orrico et al. 2004. PubMed ID: 14560308; White et al. 2017. PubMed ID: 29276006). This variant is reported in 1.5% of alleles in individuals of European (Finnish) descent in gnomAD; however, this variant is located in a region of poor sequence quality making population frequency estimates unreliable (http://gnomad.broadinstitute.org/variant/X-54497147-T-TG). Frameshift variants in FGD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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