dbSNP rs137853266: FGD1:p.Arg443Leu (chrX-54467796-C-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_004463.3(FGD1):c.1328G>T(p.Arg443Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R443H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.83

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-54467796-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521263.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant X-54467796-C-A is Pathogenic according to our data. Variant chrX-54467796-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10832.Status of the report is no_assertion_criteria_provided, 0 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.1328G>T	p.Arg443Leu	missense	Exon 6 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.1328G>T	p.Arg443Leu	missense	Exon 6 of 18	ENSP00000364277.3	P98174
FGD1	ENST00000934021.1		c.1328G>T	p.Arg443Leu	missense	Exon 6 of 19	ENSP00000604080.1
FGD1	ENST00000934019.1		c.1328G>T	p.Arg443Leu	missense	Exon 6 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1054560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

345026

African (AFR)

AF:

0.00

AC:

AN:

24951

American (AMR)

AF:

0.00

AC:

AN:

27971

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18644

East Asian (EAS)

AF:

0.00

AC:

AN:

27177

South Asian (SAS)

AF:

0.00

AC:

AN:

49895

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37687

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4085

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

819742

Other (OTH)

AF:

0.00

AC:

AN:

44408

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aarskog syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.5

PhyloP100

7.8

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.99

Vest4

0.95

MutPred

0.90

Loss of disorder (P = 0.0298)

MVP

0.98

MPC

2.5

ClinPred

1.0

GERP RS

5.2

Varity_R

0.85

gMVP

0.97

Mutation Taster

=17/83

disease causing (ClinVar)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over