Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001370298.3(FGD4):c.1716G>A(p.Arg572Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,613,716 control chromosomes in the GnomAD database, including 72,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6102 hom., cov: 33)

Exomes 𝑓: 0.30 ( 66660 hom. )

Consequence

FGD4
NM_001370298.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0900

Publications

16 publications found

Variant links:

Genes affected

FGD4 (HGNC:19125): (FYVE, RhoGEF and PH domain containing 4) This gene encodes a protein that is involved in the regulation of the actin cytoskeleton and cell shape. This protein contains an actin filament-binding domain, which together with its Dbl homology domain and one of its pleckstrin homology domains, can form microspikes. This protein can activate MAPK8 independently of the actin filament-binding domain, and it is also involved in the activation of CDC42 via the exchange of bound GDP for free GTP. The activation of CDC42 also enables this protein to play a role in mediating the cellular invasion of Cryptosporidium parvum, an intracellular parasite that infects the gastrointestinal tract. Mutations in this gene can cause Charcot-Marie-Tooth disease type 4H (CMT4H), a disorder of the peripheral nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

FGD4 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 4H
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

FGD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 12-32611250-G-A is Benign according to our data. Variant chr12-32611250-G-A is described in ClinVar as Benign. ClinVar VariationId is 137368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.09 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370298.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGD4	NM_001370298.3	MANE Select	c.1716G>A	p.Arg572Arg	synonymous	Exon 10 of 17	NP_001357227.2
FGD4	NM_001384126.1		c.1716G>A	p.Arg572Arg	synonymous	Exon 10 of 18	NP_001371055.1
FGD4	NM_001304481.2		c.1560G>A	p.Arg520Arg	synonymous	Exon 10 of 17	NP_001291410.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGD4	ENST00000534526.7	TSL:5 MANE Select	c.1716G>A	p.Arg572Arg	synonymous	Exon 10 of 17	ENSP00000449273.1
FGD4	ENST00000395740.5	TSL:1	n.*697G>A		non_coding_transcript_exon	Exon 11 of 17	ENSP00000379089.1
FGD4	ENST00000395740.5	TSL:1	n.*697G>A		3_prime_UTR	Exon 11 of 17	ENSP00000379089.1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42310

AN:

151944

Hom.:

6093

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.294

Gnomad ASJ

AF:

0.369

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.405

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.316

GnomAD2 exomes

AF:

0.293

AC:

73790

AN:

251448

AF XY:

0.306

show subpopulations

Gnomad AFR exome

AF:

0.231

Gnomad AMR exome

AF:

0.259

Gnomad ASJ exome

AF:

0.375

Gnomad EAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.307

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.298

AC:

435984

AN:

1461654

Hom.:

66660

Cov.:

AF XY:

0.304

AC XY:

221089

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.234

AC:

7819

AN:

33478

American (AMR)

AF:

0.261

AC:

11688

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

9569

AN:

26132

East Asian (EAS)

AF:

0.163

AC:

6483

AN:

39694

South Asian (SAS)

AF:

0.411

AC:

35449

AN:

86252

European-Finnish (FIN)

AF:

0.236

AC:

12598

AN:

53410

Middle Eastern (MID)

AF:

0.366

AC:

2110

AN:

5768

European-Non Finnish (NFE)

AF:

0.299

AC:

332248

AN:

1111812

Other (OTH)

AF:

0.298

AC:

18020

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

17452

34904

52357

69809

87261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10922

21844

32766

43688

54610

<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:

0.278

AC:

42342

AN:

152062

Hom.:

6102

Cov.:

AF XY:

0.279

AC XY:

20724

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.232

AC:

9626

AN:

41462

American (AMR)

AF:

0.293

AC:

4482

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

1280

AN:

3468

East Asian (EAS)

AF:

0.160

AC:

829

AN:

5174

South Asian (SAS)

AF:

0.406

AC:

1958

AN:

4824

European-Finnish (FIN)

AF:

0.223

AC:

2357

AN:

10558

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.303

AC:

20587

AN:

67970

Other (OTH)

AF:

0.317

AC:

670

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1598

3196

4793

6391

7989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.302

Hom.:

11689

Bravo

AF:

0.279

Asia WGS

AF:

0.294

AC:

1024

AN:

3478

EpiCase

AF:

0.314

EpiControl

AF:

0.326

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 4H (3)

not specified (3)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.3

(source)

DANN

Benign

0.57

PhyloP100

0.090

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs10844253

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over