X-54470714-TGGGG-TGGGGGGGGGGGGGGGGCTCGAGGGGGG

Variant names:

• chrX-54470714-T-TGGGGGGGGGGGGGGGGCTCGAGG
• rs756586058
• NM_004463.3:c.527_528insCCTCGAGCCCCCCCCCCCCCCCC

Variant summary

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

The NM_004463.3(FGD1):​c.527_528insCCTCGAGCCCCCCCCCCCCCCCC​(p.Ile180ProfsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: 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
• 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 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 rank	MANE	Protein	UniProt
FGD1	NM_004463.3	c.527_528insCCTCGAGCCCCCCCCCCCCCCCC	p.Ile180ProfsTer43	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.527_528insCCTCGAGCCCCCCCCCCCCCCCC	p.Ile180ProfsTer43	frameshift_variant	Exon 3 of 18	1	NM_004463.3	ENSP00000364277.3

Frequencies

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

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

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

African (AFR) AF: 0.00 AC: 0 AN: 1848

American (AMR) AF: 0.00142 AC: 1 AN: 702

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: 189

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: 4092

Other (OTH) AF: 0.00 AC: 0 AN: 109

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;