rs749593888

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-54470207-C-T
• chrX-54470207-C-G

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>A​(p.Gly304Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000166 in 1,205,960 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: FGD1 NM_004463.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.13
• Publications: 1 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=0.21653229).

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>A	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>A	p.Gly304Arg	missense	Exon 4 of 18	ENSP00000364277.3	P98174
	FGD1	ENST00000934021.1		c.910G>A	p.Gly304Arg	missense	Exon 4 of 19	ENSP00000604080.1
	FGD1	ENST00000934019.1		c.910G>A	p.Gly304Arg	missense	Exon 4 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112064 Hom.: 0 Cov.: 23

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000589 AC: 1 AN: 169658 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093896 Hom.: 0 Cov.: 33 AF XY: 0.00000278 AC XY: 1 AN XY: 359802

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: 0.00000119 AC: 1 AN: 839962

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

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112064 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34246

African (AFR) AF: 0.00 AC: 0 AN: 30898

American (AMR) AF: 0.00 AC: 0 AN: 10633

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.00 AC: 0 AN: 2647

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53126

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

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	0.84	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.079	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		0.24	B
Vest4		0.32
MutPred		0.29		Loss of sheet (P = 0.0457)
MVP		0.74
MPC		0.36
ClinPred		0.61	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)		0.010		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; COSMIC: COSV100911122;