NM_004463.3:c.395G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004463.3(FGD1):c.395G>A(p.Arg132Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00196 in 1,209,766 control chromosomes in the GnomAD database, including 1 homozygotes. There are 720 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 43 hem., cov: 23)

Exomes 𝑓: 0.0020 ( 1 hom. 677 hem. )

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.86

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061568916).

BP6

Variant X-54471400-C-T is Benign according to our data. Variant chrX-54471400-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 140 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.395G>A	p.Arg132Gln	missense_variant	Exon 2 of 18	ENST00000375135.4	NP_004454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 link	c.395G>A	p.Arg132Gln	missense_variant	Exon 2 of 18	1	NM_004463.3	ENSP00000364277.3

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

140

AN:

112555

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000938

Gnomad ASJ

AF:

0.000753

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.000365

Gnomad FIN

AF:

0.000483

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.00198

GnomAD2 exomes

AF:

0.00132

AC:

242

AN:

183402

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000729

Gnomad ASJ exome

AF:

0.000935

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00100

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00204

AC:

2236

AN:

1097161

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

677

AN XY:

362863

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26368

American (AMR)

AF:

0.000909

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.000826

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.000111

AC:

AN:

54106

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

40529

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

3576

European-Non Finnish (NFE)

AF:

0.00245

AC:

2065

AN:

841764

Other (OTH)

AF:

0.00130

AC:

AN:

46026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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

AF:

0.00124

AC:

140

AN:

112605

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

34769

show subpopulations

African (AFR)

AF:

0.000322

AC:

AN:

31031

American (AMR)

AF:

0.000937

AC:

AN:

10675

Ashkenazi Jewish (ASJ)

AF:

0.000753

AC:

AN:

2657

East Asian (EAS)

AF:

0.000281

AC:

AN:

3559

South Asian (SAS)

AF:

0.000366

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.000483

AC:

AN:

6210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00206

AC:

110

AN:

53301

Other (OTH)

AF:

0.00195

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00188

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00381

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00312

AC:

ExAC

AF:

0.00135

AC:

164

EpiCase

AF:

0.00234

EpiControl

AF:

0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aarskog syndrome

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 29, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 07, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FGD1-related disorder

Benign:1

Aug 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Jul 27, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

M_CAP

Benign

0.044

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.34

PhyloP100

4.9

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.80

REVEL

Benign

0.091

Sift

Uncertain

0.011

Sift4G

Benign

0.26

Polyphen

0.50

Vest4

0.14

MVP

0.58

MPC

0.33

ClinPred

0.015

GERP RS

4.9

Varity_R

0.22

gMVP

0.080

Mutation Taster

=90/10

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over