X-54470714-TGGGG-TGGGGGG

Variant names:

• chrX-54470714-T-TGG
• rs756586058
• NM_004463.3:c.526_527dupCC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_004463.3(FGD1):​c.526_527dupCC​(p.Leu177HisfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 19)
  • Exomes 𝑓: 0.000011 (0 hom. 0 hem.)
• Consequence: FGD1 NM_004463.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452
• Publications: 0 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 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.526_527dupCC	p.Leu177HisfsTer39	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.526_527dupCC	p.Leu177HisfsTer39	frameshift	Exon 3 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.526_527dupCC	p.Leu177HisfsTer39	frameshift	Exon 3 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.526_527dupCC	p.Leu177HisfsTer39	frameshift	Exon 3 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.0000111 AC: 2 AN: 179849 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 37555

African (AFR) AF: 0.00 AC: 0 AN: 5661

American (AMR) AF: 0.000142 AC: 1 AN: 7065

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4752

East Asian (EAS) AF: 0.00 AC: 0 AN: 10153

South Asian (SAS) AF: 0.00 AC: 0 AN: 9864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 925

European-Non Finnish (NFE) AF: 0.00000840 AC: 1 AN: 119031

Other (OTH) AF: 0.00 AC: 0 AN: 8914

GnomAD4 genome Cov.: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756586058; hg19: chrX-54497147;