X-54470714-TGG-TGGG

Variant names:

• chrX-54470714-T-TG
• rs756586058
• NM_004463.3:c.527dupC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004463.3(FGD1):​c.527dupC​(p.Leu177ThrfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.452

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 Pathogenic. Variant got 16 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.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 7879 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 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.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 36504

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: 0 AN: 7912 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 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.: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

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. -

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

- -

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 -

Aarskog syndrome Pathogenic:5

Jan 03, 2022

3billion, Medical Genetics

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. -

Jun 01, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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). -

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

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

Other links and lift over

dbSNP: rs756586058; hg19: chrX-54497147;