Genetic Variant FGD1:p.Gln333Lys (chrX-54470120-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004463.3(FGD1):c.997C>A(p.Gln333Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,260 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.66

Publications

0 publications found

Variant links:

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

FGD1 links:

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ACMG classification

Classification was made for transcript

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=0.107082784).

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.997C>A	p.Gln333Lys	missense	Exon 4 of 18	NP_004454.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGD1	ENST00000375135.4	TSL:1 MANE Select	c.997C>A	p.Gln333Lys	missense	Exon 4 of 18	ENSP00000364277.3	P98174
FGD1	ENST00000934021.1		c.997C>A	p.Gln333Lys	missense	Exon 4 of 19	ENSP00000604080.1
FGD1	ENST00000934019.1		c.997C>A	p.Gln333Lys	missense	Exon 4 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097260

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26391

American (AMR)

AF:

0.00

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.00

AC:

AN:

53966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841501

Other (OTH)

AF:

0.00

AC:

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.76

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

1.7

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

REVEL

Benign

0.086

Sift

Benign

0.16

Sift4G

Benign

0.46

Polyphen

0.0010

Vest4

0.15

MutPred

0.31

Gain of ubiquitination at Q333 (P = 6e-04)

MVP

0.65

MPC

0.36

ClinPred

0.086

GERP RS

1.9

Varity_R

0.22

gMVP

0.42

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over