chrX-54470714-TG-T

Variant names:

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

Variant summary

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

The NM_004463.3(FGD1):​c.527delC​(p.Pro176HisfsTer39) 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: 0.0011 (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:9
• 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-TG-T is Pathogenic according to our data. Variant chrX-54470714-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54470714-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3	c.527delC	p.Pro176HisfsTer39	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.527delC	p.Pro176HisfsTer39	frameshift_variant	Exon 3 of 18	1	NM_004463.3	ENSP00000364277.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 7890 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 1370 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: 0.00110 AC: 197 AN: 178387 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 36891

Gnomad4 AFR exome AF: 0.00178

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.000846

Gnomad4 EAS exome AF: 0.000198

Gnomad4 SAS exome AF: 0.000102

Gnomad4 FIN exome AF: 0.000223

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 7890 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 1370

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aarskog syndrome Pathogenic:6

May 12, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 3 of 18). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar, Orrico, A. et al. (2010)). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Dec 19, 2014

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Our laboratory reported dual molecular diagnoses in PAFAH1B1 (NM_000430.3, c.484G>A) and FGD1 (NM_004463.2, c.527delC) in this individual with reported features of intrauterine growth restriction, delayed motor milestones, delayed speech, autism, intellectual disability, hearing loss, hypotonia, seizure disorder, ataxia, dysmorphic features, short stature, microcephaly, failure to thrive, eye anomalies, skeletal abnormalities and scoliosis, and structural brain anomalies. The PAFAH1B1 variant has been reported in one patient with a mild LIS1 phenotype [PMID: 11115846, 12885786]. The FGD1 variant is predicted to cause a frameshift and is categorized as deleterious by ACMGG guidelines [PMID: 18414213]. -

Aug 15, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide deletion in exon 3 of 18 of the FGD1 gene that results in an early termition codon 39 amino acids downstream of the frameshift at codon 176. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of FGD1 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 374329) that has been observed in the literature in an individual with phenotypes consistent with Aarskog-Scott syndrome (PMID: 27959697). This variant is absent from the gnomAD population database (0/~131000 alleles). Haploinsufficiency in FGD1 is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PVS1 -

Apr 27, 2020

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1 -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jul 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27959697, 34189097) -

Nov 06, 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.Pro176Hisfs*39) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with FGD1-related conditions (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374329). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Mar 09, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.527delC pathogenic mutation, located in coding exon 3 of the FGD1 gene, results from a deletion of one nucleotide at nucleotide position 527, causing a translational frameshift with a predicted alternate stop codon (p.P176Hfs*39). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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;