rs1126744

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54449671-T-C is described in Lovd as [Likely_benign].

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.:

AF XY:

0.130

AC XY:

4170

AN XY:

32064

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

GnomAD3 exomes

AF:

0.0670

AC:

11999

AN:

179080

Hom.:

1148

AF XY:

0.0587

AC XY:

3746

AN XY:

63864

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 SAS exome

AF:

0.0957

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

Gnomad4 AFR exome

AF:

0.432

Gnomad4 AMR exome

AF:

0.0391

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.0887

Gnomad4 SAS exome

AF:

0.0950

Gnomad4 FIN exome

AF:

0.0277

Gnomad4 NFE exome

AF:

0.0167

Gnomad4 OTH exome

AF:

0.0641

GnomAD4 genome

AF:

0.141

AC:

15431

AN:

109818

Hom.:

2127

Cov.:

AF XY:

0.130

AC XY:

4185

AN XY:

32130

show subpopulations

Gnomad4 AFR

AF:

0.424

Gnomad4 AMR

AF:

0.0710

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.0974

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.0254

Gnomad4 NFE

AF:

0.0191

Gnomad4 OTH

AF:

0.127

Alfa

AF:

0.0611

Hom.:

1314

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 28, 2018	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2014

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

DANN

Benign

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over