X-54470714-TGGGG-TGGGGG

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_004463.3(FGD1):c.527dupC(p.Leu177ThrfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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
NM_004463.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.452

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

Aarskog-Scott syndrome, X-linked
Inheritance: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

FGD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196389.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.527dupC	p.Leu177ThrfsTer40	frameshift_variant	Exon 3 of 18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 link	c.527dupC	p.Leu177ThrfsTer40	frameshift_variant	Exon 3 of 18	1	NM_004463.3	ENSP00000364277.3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

7879

Hom.:

Cov.:

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00285

AC:

AN:

5616

American (AMR)

AF:

0.00142

AC:

AN:

7030

Ashkenazi Jewish (ASJ)

AF:

0.00106

AC:

AN:

4713

East Asian (EAS)

AF:

0.00129

AC:

AN:

10079

South Asian (SAS)

AF:

0.000919

AC:

AN:

9798

European-Finnish (FIN)

AF:

0.00127

AC:

AN:

13347

Middle Eastern (MID)

AF:

0.00219

AC:

AN:

915

European-Non Finnish (NFE)

AF:

0.00316

AC:

370

AN:

117032

Other (OTH)

AF:

0.00227

AC:

AN:

8806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

African (AFR)

AF:

0.00

AC:

AN:

1862

American (AMR)

AF:

0.00

AC:

AN:

705

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

218

East Asian (EAS)

AF:

0.00

AC:

AN:

324

South Asian (SAS)

AF:

0.00

AC:

AN:

187

European-Finnish (FIN)

AF:

0.00

AC:

AN:

336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

4090

Other (OTH)

AF:

0.00

AC:

AN:

116

Alfa

AF:

0.000994

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aarskog syndrome

Pathogenic:6

Jan 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 13, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

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). -

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 02, 2024

Istanbul Faculty of Medicine, Istanbul University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

PM3, PVS1 -

Jun 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:5

Sep 13, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Jun 05, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). 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 premature translational stop signal has been observed in individual(s) with FGD1-related conditions (PMID: 14560308, 29276006). ClinVar contains an entry for this variant (Variation ID: 196389). For these reasons, this variant has been classified as Pathogenic. -

Jan 26, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PS4_Moderate -

FGD1-related disorder

Pathogenic:1

Jul 26, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PhyloP100

0.45

Mutation Taster

=9/191

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over