rs12011120

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.2091T>C(p.Thr697Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,206,541 control chromosomes in the GnomAD database, including 6,368 homozygotes. There are 18,988 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 3067 hom., 5010 hem., cov: 22)

Exomes 𝑓: 0.039 ( 3301 hom. 13978 hem. )

Consequence

FGD1
NM_004463.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.400

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=-0.63).

BP6

Variant X-54449716-A-G is Benign according to our data. Variant chrX-54449716-A-G is described in ClinVar as [Benign]. Clinvar id is 95086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54449716-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.4 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.2091T>C	p.Thr697Thr	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.2091T>C	p.Thr697Thr	synonymous_variant	Exon 14 of 18	1	NM_004463.3	ENSP00000364277.3		P98174

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

18294

AN:

110312

Hom.:

3064

Cov.:

AF XY:

0.153

AC XY:

4989

AN XY:

32564

show subpopulations

Gnomad AFR

AF:

0.515

Gnomad AMI

AF:

0.00587

Gnomad AMR

AF:

0.0781

Gnomad ASJ

AF:

0.0155

Gnomad EAS

AF:

0.0982

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.0252

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.137

GnomAD3 exomes

AF:

0.0743

AC:

13586

AN:

182735

Hom.:

1559

AF XY:

0.0644

AC XY:

4329

AN XY:

67229

show subpopulations

Gnomad AFR exome

AF:

0.529

Gnomad AMR exome

AF:

0.0398

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.0964

Gnomad SAS exome

AF:

0.0999

Gnomad FIN exome

AF:

0.0288

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0485

GnomAD4 exome

AF:

0.0391

AC:

42812

AN:

1096173

Hom.:

3301

Cov.:

AF XY:

0.0386

AC XY:

13978

AN XY:

361799

show subpopulations

Gnomad4 AFR exome

AF:

0.526

Gnomad4 AMR exome

AF:

0.0443

Gnomad4 ASJ exome

AF:

0.0189

Gnomad4 EAS exome

AF:

0.0894

Gnomad4 SAS exome

AF:

0.0968

Gnomad4 FIN exome

AF:

0.0278

Gnomad4 NFE exome

AF:

0.0173

Gnomad4 OTH exome

AF:

0.0706

GnomAD4 genome

AF:

0.166

AC:

18323

AN:

110368

Hom.:

3067

Cov.:

AF XY:

0.154

AC XY:

5010

AN XY:

32630

show subpopulations

Gnomad4 AFR

AF:

0.514

Gnomad4 AMR

AF:

0.0780

Gnomad4 ASJ

AF:

0.0155

Gnomad4 EAS

AF:

0.0979

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.0252

Gnomad4 NFE

AF:

0.0192

Gnomad4 OTH

AF:

0.139

Alfa

AF:

0.0507

Hom.:

2220

Bravo

AF:

0.188

EpiCase

AF:

0.0229

EpiControl

AF:

0.0225

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.Thr697Thr 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 52.77% (4481/8491) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs12011120). -

Nov 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

May 04, 2021

GeneDx

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

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 12, 2015

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

-0.63

CADD

Benign

7.4

DANN

Benign

0.76

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