Genetic Variant FGD1:c.-4G>C (chrX-54495436-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

3 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 -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 VariationId is 95077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004463.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD1	NM_004463.3	MANE Select	c.-4G>C		5_prime_UTR	Exon 1 of 18	NP_004454.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGD1	ENST00000375135.4	TSL:1 MANE Select	c.-4G>C	5_prime_UTR	Exon 1 of 18	ENSP00000364277.3	P98174
FGD1	ENST00000934021.1		c.-4G>C	5_prime_UTR	Exon 1 of 19	ENSP00000604080.1
FGD1	ENST00000934019.1		c.-4G>C	5_prime_UTR	Exon 1 of 18	ENSP00000604078.1

Frequencies

GnomAD3 genomes

AF:

0.0504

AC:

5563

AN:

110276

Hom.:

173

Cov.:

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

GnomAD2 exomes

AF:

0.254

AC:

1525

AN:

5995

AF XY:

0.534

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 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

African (AFR)

AF:

0.0101

AC:

182

AN:

18083

American (AMR)

AF:

0.0352

AC:

266

AN:

7558

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

960

AN:

11729

East Asian (EAS)

AF:

0.000192

AC:

AN:

20822

South Asian (SAS)

AF:

0.138

AC:

3692

AN:

26710

European-Finnish (FIN)

AF:

0.0967

AC:

2062

AN:

21333

Middle Eastern (MID)

AF:

0.0726

AC:

164

AN:

2260

European-Non Finnish (NFE)

AF:

0.0883

AC:

66090

AN:

748106

Other (OTH)

AF:

0.0715

AC:

2653

AN:

37114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2227

4454

6680

8907

11134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2640

5280

7920

10560

13200

<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:

0.0503

AC:

5553

AN:

110318

Hom.:

172

Cov.:

AF XY:

0.0471

AC XY:

1550

AN XY:

32922

show subpopulations

African (AFR)

AF:

0.0113

AC:

347

AN:

30585

American (AMR)

AF:

0.0228

AC:

243

AN:

10653

Ashkenazi Jewish (ASJ)

AF:

0.0675

AC:

177

AN:

2622

East Asian (EAS)

AF:

0.000585

AC:

AN:

3420

South Asian (SAS)

AF:

0.0749

AC:

197

AN:

2630

European-Finnish (FIN)

AF:

0.0778

AC:

451

AN:

5797

Middle Eastern (MID)

AF:

0.0290

AC:

AN:

207

European-Non Finnish (NFE)

AF:

0.0769

AC:

4015

AN:

52237

Other (OTH)

AF:

0.0401

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

189

377

566

754

943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0629

Hom.:

448

Bravo

AF:

0.0449

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

-0.090

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over