chrX-54470207-C-G

Variant names:

• chrX-54470207-C-G
• rs749593888
• NM_004463.3:c.910G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004463.3(FGD1):​c.910G>C​(p.Gly304Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000366 in 1,093,896 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 0 hem.)
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21953171).

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.910G>C	p.Gly304Arg	missense	Exon 4 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.910G>C	p.Gly304Arg	missense	Exon 4 of 18	ENSP00000364277.3
	FGD1	ENST00000934021.1		c.910G>C	p.Gly304Arg	missense	Exon 4 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.910G>C	p.Gly304Arg	missense	Exon 4 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1093896 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 359802

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

African (AFR) AF: 0.00 AC: 0 AN: 26358

American (AMR) AF: 0.00 AC: 0 AN: 34762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19264

East Asian (EAS) AF: 0.00 AC: 0 AN: 30050

South Asian (SAS) AF: 0.00 AC: 0 AN: 53330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40149

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 839962

Other (OTH) AF: 0.00 AC: 0 AN: 45893

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000266003), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.23
Sift	Benign	0.046	D
Sift4G	Uncertain	0.033	D
Polyphen		0.13	B
Vest4		0.32
MutPred		0.29		Loss of sheet (P = 0.0457)
MVP		0.72
MPC		0.36
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.35
gMVP		0.40
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs749593888; hg19: chrX-54496640;