X-54470441-C-T

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.676G>A(p.Ala226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,203,728 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., 99 hem., cov: 23)

Exomes 𝑓: 0.0033 ( 8 hom. 1070 hem. )

Consequence

FGD1
NM_004463.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0210

Publications

4 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=0.004192412).

BP6

Variant X-54470441-C-T is Benign according to our data. Variant chrX-54470441-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 281 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.676G>A	p.Ala226Thr	missense_variant	Exon 4 of 18	ENST00000375135.4	NP_004454.2	P98174A0A024R9Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 link	c.676G>A	p.Ala226Thr	missense_variant	Exon 4 of 18	1	NM_004463.3	ENSP00000364277.3		P98174

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

281

AN:

111497

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000457

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00653

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.00362

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00323

Gnomad OTH

AF:

0.00201

GnomAD2 exomes

AF:

0.00268

AC:

463

AN:

172713

AF XY:

0.00212

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.00288

Gnomad ASJ exome

AF:

0.000814

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00460

Gnomad NFE exome

AF:

0.00383

Gnomad OTH exome

AF:

0.00371

GnomAD4 exome

AF:

0.00328

AC:

3581

AN:

1092179

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

1070

AN XY:

359709

show subpopulations

African (AFR)

AF:

0.000304

AC:

AN:

26352

American (AMR)

AF:

0.00265

AC:

AN:

35133

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

19342

East Asian (EAS)

AF:

0.00

AC:

AN:

30119

South Asian (SAS)

AF:

0.0000932

AC:

AN:

53653

European-Finnish (FIN)

AF:

0.00441

AC:

160

AN:

36257

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00375

AC:

3157

AN:

841219

Other (OTH)

AF:

0.00300

AC:

138

AN:

45971

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

143

285

428

570

713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00252

AC:

281

AN:

111549

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

AN XY:

33775

show subpopulations

African (AFR)

AF:

0.000456

AC:

AN:

30697

American (AMR)

AF:

0.00653

AC:

AN:

10573

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3497

South Asian (SAS)

AF:

0.000376

AC:

AN:

2657

European-Finnish (FIN)

AF:

0.00362

AC:

AN:

6074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00323

AC:

171

AN:

52998

Other (OTH)

AF:

0.00199

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00300

Hom.:

133

Bravo

AF:

0.00252

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00381

AC:

ESP6500AA

AF:

0.000523

AC:

ESP6500EA

AF:

0.00343

AC:

ExAC

AF:

0.00231

AC:

280

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 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

- -

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

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 27, 2017

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

Feb 28, 2020

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

Dec 30, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.066

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.65

M_CAP

Benign

0.013

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-0.021

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.49

REVEL

Benign

0.036

Sift

Benign

0.19

Sift4G

Benign

0.78

Polyphen

0.012

Vest4

0.017

MVP

0.28

MPC

0.30

ClinPred

0.011

GERP RS

1.5

Varity_R

0.048

gMVP

0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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