dbSNP rs2071812: FGD1:c.1636+21C>T (chrX-54465430-G-A) – 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.1636+21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00938 in 1,196,170 control chromosomes in the GnomAD database, including 291 homozygotes. There are 3,733 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 39 hom., 418 hem., cov: 21)

Exomes 𝑓: 0.0091 ( 252 hom. 3315 hem. )

Consequence

FGD1
NM_004463.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.67

Publications

2 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=-0.78).

BP6

Variant X-54465430-G-A is Benign according to our data. Variant chrX-54465430-G-A is described in ClinVar as Benign. ClinVar VariationId is 259402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD1	NM_004463.3 link	c.1636+21C>T		intron_variant	Intron 8 of 17	ENST00000375135.4	NP_004454.2	P98174A0A024R9Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD1	ENST00000375135.4 link	c.1636+21C>T		intron_variant	Intron 8 of 17	1	NM_004463.3	ENSP00000364277.3		P98174

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1328

AN:

110050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00382

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0632

Gnomad ASJ

AF:

0.000380

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.00378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00167

Gnomad OTH

AF:

0.0228

GnomAD2 exomes

AF:

0.0265

AC:

4534

AN:

171389

AF XY:

0.0228

show subpopulations

Gnomad AFR exome

AF:

0.00354

Gnomad AMR exome

AF:

0.0829

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00209

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.00911

AC:

9893

AN:

1086067

Hom.:

252

Cov.:

AF XY:

0.00935

AC XY:

3315

AN XY:

354671

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

26222

American (AMR)

AF:

0.0834

AC:

2897

AN:

34732

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

18513

East Asian (EAS)

AF:

0.103

AC:

3086

AN:

30057

South Asian (SAS)

AF:

0.0258

AC:

1342

AN:

52016

European-Finnish (FIN)

AF:

0.00345

AC:

138

AN:

40024

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

4061

European-Non Finnish (NFE)

AF:

0.00210

AC:

1754

AN:

834847

Other (OTH)

AF:

0.0128

AC:

582

AN:

45595

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

331

662

993

1324

1655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.0121

AC:

1330

AN:

110103

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

418

AN XY:

32387

show subpopulations

African (AFR)

AF:

0.00381

AC:

116

AN:

30412

American (AMR)

AF:

0.0634

AC:

654

AN:

10308

Ashkenazi Jewish (ASJ)

AF:

0.000380

AC:

AN:

2633

East Asian (EAS)

AF:

0.107

AC:

361

AN:

3366

South Asian (SAS)

AF:

0.0215

AC:

AN:

2512

European-Finnish (FIN)

AF:

0.00378

AC:

AN:

5823

Middle Eastern (MID)

AF:

0.00

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.00167

AC:

AN:

52659

Other (OTH)

AF:

0.0225

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00577

Hom.:

Bravo

AF:

0.0188

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 20, 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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.1

(source)

DANN

Benign

0.67

PhyloP100

1.7

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over