rs147035080

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004463.3(FGD1):c.-4G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0813 in 1,004,033 control chromosomes in the GnomAD database, including 2,344 homozygotes. There are 25,995 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 172 hom., 1550 hem., cov: 22)

Exomes 𝑓: 0.085 ( 2172 hom. 24445 hem. )

Consequence

FGD1
NM_004463.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0900

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant X-54495436-C-G is Benign according to our data. Variant chrX-54495436-C-G is described in ClinVar as [Benign]. Clinvar id is 95077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54495436-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.-4G>C		5_prime_UTR_variant	Exon 1 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.-4G>C		5_prime_UTR_variant	Exon 1 of 18	1	NM_004463.3	ENSP00000364277.3		P98174

Frequencies

GnomAD3 genomes

AF:

0.0504

AC:

5563

AN:

110276

Hom.:

173

Cov.:

AF XY:

0.0473

AC XY:

1556

AN XY:

32870

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.0835

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.0675

Gnomad EAS

AF:

0.000583

Gnomad SAS

AF:

0.0769

Gnomad FIN

AF:

0.0778

Gnomad MID

AF:

0.0307

Gnomad NFE

AF:

0.0769

Gnomad OTH

AF:

0.0413

GnomAD3 exomes

AF:

0.254

AC:

1525

AN:

5995

Hom.:

AF XY:

0.534

AC XY:

383

AN XY:

717

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.435

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.386

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.261

GnomAD4 exome

AF:

0.0851

AC:

76073

AN:

893715

Hom.:

2172

Cov.:

AF XY:

0.0896

AC XY:

24445

AN XY:

272959

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

Gnomad4 AMR exome

AF:

0.0352

Gnomad4 ASJ exome

AF:

0.0818

Gnomad4 EAS exome

AF:

0.000192

Gnomad4 SAS exome

AF:

0.138

Gnomad4 FIN exome

AF:

0.0967

Gnomad4 NFE exome

AF:

0.0883

Gnomad4 OTH exome

AF:

0.0715

GnomAD4 genome

AF:

0.0503

AC:

5553

AN:

110318

Hom.:

172

Cov.:

AF XY:

0.0471

AC XY:

1550

AN XY:

32922

show subpopulations

Gnomad4 AFR

AF:

0.0113

Gnomad4 AMR

AF:

0.0228

Gnomad4 ASJ

AF:

0.0675

Gnomad4 EAS

AF:

0.000585

Gnomad4 SAS

AF:

0.0749

Gnomad4 FIN

AF:

0.0778

Gnomad4 NFE

AF:

0.0769

Gnomad4 OTH

AF:

0.0401

Alfa

AF:

0.0629

Hom.:

448

Bravo

AF:

0.0449

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 17, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.-4G>C in the 5'UTR of FGD1: This variant is is not expected to have clinical significance because it has been identified in 9.8% (2533/25820) of total chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147035080). ACMG/AMP Criteria applied: BA1 -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

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

Nov 24, 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

-0.53

CADD

Benign

DANN

Benign

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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