dbSNP rs60803891: FGD4:p.Ser642Ser (chr12-32624425-T-C) – ACMG Classification: Benign (-19 pts)

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.1926T>C(p.Ser642Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,601,258 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 51 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 48 hom. )

Consequence

FGD4
NM_001370298.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.81

Publications

1 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=-0.46).

BP6

Variant 12-32624425-T-C is Benign according to our data. Variant chr12-32624425-T-C is described in ClinVar as Benign. ClinVar VariationId is 308298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.81 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 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	UniProt
FGD4	NM_001370298.3	MANE Select	c.1926T>C	p.Ser642Ser	synonymous	Exon 12 of 17	NP_001357227.2	F8VWL3
FGD4	NM_001384126.1		c.1926T>C	p.Ser642Ser	synonymous	Exon 12 of 18	NP_001371055.1
FGD4	NM_001304481.2		c.1770T>C	p.Ser590Ser	synonymous	Exon 12 of 17	NP_001291410.1	B7Z493

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGD4	ENST00000534526.7	TSL:5 MANE Select	c.1926T>C	p.Ser642Ser	synonymous	Exon 12 of 17	ENSP00000449273.1	F8VWL3
FGD4	ENST00000395740.5	TSL:1	n.*907T>C		non_coding_transcript_exon	Exon 13 of 17	ENSP00000379089.1	E9PNX0
FGD4	ENST00000395740.5	TSL:1	n.*907T>C		3_prime_UTR	Exon 13 of 17	ENSP00000379089.1	E9PNX0

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2284

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00701

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00383

AC:

948

AN:

247666

AF XY:

0.00269

show subpopulations

Gnomad AFR exome

AF:

0.0506

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00160

AC:

2322

AN:

1448990

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

998

AN XY:

721128

show subpopulations

African (AFR)

AF:

0.0525

AC:

1745

AN:

33236

American (AMR)

AF:

0.00321

AC:

143

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25926

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.0000936

AC:

AN:

85428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53232

Middle Eastern (MID)

AF:

0.00454

AC:

AN:

5284

European-Non Finnish (NFE)

AF:

0.000162

AC:

178

AN:

1101862

Other (OTH)

AF:

0.00372

AC:

223

AN:

59878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0151

AC:

2293

AN:

152268

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1115

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0515

AC:

2138

AN:

41546

American (AMR)

AF:

0.00700

AC:

107

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68024

Other (OTH)

AF:

0.0128

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

108

216

325

433

541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00746

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 4H (2)

not provided (2)

not specified (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

FGD4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

1.8

Mutation Taster

=95/5

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.

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