Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The ENST00000534526.7(FGD4):c.2070C>G(p.Ala690Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 1,613,582 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A690A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00076 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

FGD4
ENST00000534526.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.384

Publications

0 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=-0.35).

BP6

Variant 12-32625677-C-G is Benign according to our data. Variant chr12-32625677-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.384 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000764 (116/151752) while in subpopulation EAS AF = 0.0143 (74/5176). AF 95% confidence interval is 0.0117. There are 2 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000534526.7. 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.2070C>G	p.Ala690Ala	synonymous	Exon 14 of 17	NP_001357227.2
FGD4	NM_001384126.1		c.2070C>G	p.Ala690Ala	synonymous	Exon 14 of 18	NP_001371055.1
FGD4	NM_001304481.2		c.1914C>G	p.Ala638Ala	synonymous	Exon 14 of 17	NP_001291410.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGD4	ENST00000534526.7	TSL:5 MANE Select	c.2070C>G	p.Ala690Ala	synonymous	Exon 14 of 17	ENSP00000449273.1
FGD4	ENST00000395740.5	TSL:1	n.*1051C>G		non_coding_transcript_exon	Exon 15 of 17	ENSP00000379089.1
FGD4	ENST00000395740.5	TSL:1	n.*1051C>G		3_prime_UTR	Exon 15 of 17	ENSP00000379089.1

Frequencies

GnomAD3 genomes

AF:

0.000765

AC:

116

AN:

151634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0143

Gnomad SAS

AF:

0.00250

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.00106

AC:

266

AN:

251466

AF XY:

0.000934

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000431

AC:

630

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

315

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0112

AC:

446

AN:

39688

South Asian (SAS)

AF:

0.000800

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111980

Other (OTH)

AF:

0.00156

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000764

AC:

116

AN:

151752

Hom.:

Cov.:

AF XY:

0.000756

AC XY:

AN XY:

74116

show subpopulations

African (AFR)

AF:

0.000266

AC:

AN:

41340

American (AMR)

AF:

0.00105

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.0143

AC:

AN:

5176

South Asian (SAS)

AF:

0.00250

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67934

Other (OTH)

AF:

0.000951

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000471

Hom.:

Bravo

AF:

0.000450

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

Charcot-Marie-Tooth disease type 4H (1)

FGD4-related disorder (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.3

(source)

DANN

Benign

0.69

PhyloP100

-0.38

Mutation Taster

=86/14

polymorphism

(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.

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