X-54470714-TGGGG-TGGG

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 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. 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 Likely pathogenic (★★). 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: 0.0011 (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
• 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: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 374329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.527delC	p.Pro176HisfsTer39	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.527delC	p.Pro176HisfsTer39	frameshift	Exon 3 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.527delC	p.Pro176HisfsTer39	frameshift	Exon 3 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.527delC	p.Pro176HisfsTer39	frameshift	Exon 3 of 18	ENSP00000604078.1

Frequencies

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

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

African (AFR) AF: 0.00178 AC: 10 AN: 5633

American (AMR) AF: 0.000142 AC: 1 AN: 7038

Ashkenazi Jewish (ASJ) AF: 0.000846 AC: 4 AN: 4726

East Asian (EAS) AF: 0.000198 AC: 2 AN: 10095

South Asian (SAS) AF: 0.000102 AC: 1 AN: 9815

European-Finnish (FIN) AF: 0.000223 AC: 3 AN: 13428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 924

European-Non Finnish (NFE) AF: 0.00144 AC: 170 AN: 117889

Other (OTH) AF: 0.000679 AC: 6 AN: 8839

⚠️ 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: 7890 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 1370

African (AFR) AF: 0.00 AC: 0 AN: 1846

American (AMR) AF: 0.00 AC: 0 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

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Aarskog syndrome (6)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=1/199	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: COSV64307990;