rs1126744

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004463.3(FGD1):c.2136A>G(p.Pro712Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,190,574 control chromosomes in the GnomAD database, including 4,535 homozygotes. There are 16,461 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2127 hom., 4185 hem., cov: 21)

Exomes 𝑓: 0.036 ( 2408 hom. 12276 hem. )

Consequence

FGD1
NM_004463.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.872

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant X-54449671-T-C is Benign according to our data. Variant chrX-54449671-T-C is described in ClinVar as Benign. ClinVar VariationId is 95089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.872 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.2136A>G	p.Pro712Pro	synonymous_variant	Exon 14 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.2136A>G	p.Pro712Pro	synonymous_variant	Exon 14 of 18	1	NM_004463.3	ENSP00000364277.3		P98174

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

15410

AN:

109762

Hom.:

2125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.425

Gnomad AMI

AF:

0.00590

Gnomad AMR

AF:

0.0711

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.0977

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.0254

Gnomad MID

AF:

0.0812

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.0670

AC:

11999

AN:

179080

AF XY:

0.0587

show subpopulations

Gnomad AFR exome

AF:

0.441

Gnomad AMR exome

AF:

0.0350

Gnomad ASJ exome

AF:

0.0145

Gnomad EAS exome

AF:

0.0962

Gnomad FIN exome

AF:

0.0283

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0464

GnomAD4 exome

AF:

0.0358

AC:

38667

AN:

1080756

Hom.:

2408

Cov.:

AF XY:

0.0352

AC XY:

12276

AN XY:

348276

show subpopulations

African (AFR)

AF:

0.432

AC:

11119

AN:

25759

American (AMR)

AF:

0.0391

AC:

1372

AN:

35064

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

351

AN:

19143

East Asian (EAS)

AF:

0.0887

AC:

2671

AN:

30106

South Asian (SAS)

AF:

0.0950

AC:

5061

AN:

53285

European-Finnish (FIN)

AF:

0.0277

AC:

1122

AN:

40443

Middle Eastern (MID)

AF:

0.0585

AC:

232

AN:

3966

European-Non Finnish (NFE)

AF:

0.0167

AC:

13825

AN:

827524

Other (OTH)

AF:

0.0641

AC:

2914

AN:

45466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

1022

2045

3067

4090

5112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.141

AC:

15431

AN:

109818

Hom.:

2127

Cov.:

AF XY:

0.130

AC XY:

4185

AN XY:

32130

show subpopulations

African (AFR)

AF:

0.424

AC:

12690

AN:

29906

American (AMR)

AF:

0.0710

AC:

731

AN:

10295

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

2620

East Asian (EAS)

AF:

0.0974

AC:

336

AN:

3450

South Asian (SAS)

AF:

0.104

AC:

266

AN:

2548

European-Finnish (FIN)

AF:

0.0254

AC:

149

AN:

5868

Middle Eastern (MID)

AF:

0.0837

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0191

AC:

1006

AN:

52744

Other (OTH)

AF:

0.127

AC:

190

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

349

697

1046

1394

1743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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:

0.117

Hom.:

3495

Bravo

AF:

0.159

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 28, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro712Pro in exon 14 of FGD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 44.23% (3737/8449) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1126744). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 13, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.1

(source)

DANN

Benign

0.46

PhyloP100

-0.87

Mutation Taster

=98/2

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