X-54470714-TGGGG-TGGGGG

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1
• Conservation: PhyloP100: 0.452
• Publications: 6 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004463.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.527dupC	p.Leu177ThrfsTer40	frameshift	Exon 3 of 18	NP_004454.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	ENST00000375135.4	TSL:1 MANE Select	c.527dupC	p.Leu177ThrfsTer40	frameshift	Exon 3 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.527dupC	p.Leu177ThrfsTer40	frameshift	Exon 3 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.527dupC	p.Leu177ThrfsTer40	frameshift	Exon 3 of 18	ENSP00000604078.1

Frequencies

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

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

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

African (AFR) AF: 0.00285 AC: 16 AN: 5616

American (AMR) AF: 0.00142 AC: 10 AN: 7030

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 5 AN: 4713

East Asian (EAS) AF: 0.00129 AC: 13 AN: 10079

South Asian (SAS) AF: 0.000919 AC: 9 AN: 9798

European-Finnish (FIN) AF: 0.00127 AC: 17 AN: 13347

Middle Eastern (MID) AF: 0.00219 AC: 2 AN: 915

European-Non Finnish (NFE) AF: 0.00316 AC: 370 AN: 117032

Other (OTH) AF: 0.00227 AC: 20 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.

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

African (AFR) AF: 0.00 AC: 0 AN: 1862

American (AMR) AF: 0.00 AC: 0 AN: 705

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 218

East Asian (EAS) AF: 0.00 AC: 0 AN: 324

South Asian (SAS) AF: 0.00 AC: 0 AN: 187

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 13

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4090

Other (OTH) AF: 0.00 AC: 0 AN: 116

Alfa AF: 0.000994 Hom.: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	1	-	Aarskog syndrome (8)
5	-	-	not provided (5)
1	-	-	FGD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs756586058; hg19: chrX-54497147; COSMIC: COSV64308927;