X-54470714-TGG-TGGGGGGGGGGGGGGGGCTCGAGGGG

Position:

• chrX-54470714-TGG-TGGGGGGGGGGGGGGGGCTCGAGGGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_004463.3(FGD1):​c.527_528insCCTCGAGCCCCCCCCCCCCCCCC​(p.Ile180fs) 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. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.00013 (0 hom., 0 hem., cov: 19)
• Consequence: FGD1 NM_004463.3 frameshift
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD1	NM_004463.3	c.527_528insCCTCGAGCCCCCCCCCCCCCCCC	p.Ile180fs	frameshift_variant	3/18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4	c.527_528insCCTCGAGCCCCCCCCCCCCCCCC	p.Ile180fs	frameshift_variant	3/18	1	NM_004463.3	ENSP00000364277.3

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 1 AN: 7892 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 1370

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

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 Cov.: 16

GnomAD4 genome AF: 0.000127 AC: 1 AN: 7892 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 1370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00142

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;