Genetic Variant NM_001370298.3:c.1929G>A (chr12-32624428-G-A) – 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.1929G>A(p.Ala643Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,587,558 control chromosomes in the GnomAD database, including 69,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A643A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.27 ( 5638 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63767 hom. )

Consequence

FGD4
NM_001370298.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.526

Publications

12 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=-0.38).

BP6

Variant 12-32624428-G-A is Benign according to our data. Variant chr12-32624428-G-A is described in ClinVar as Benign. ClinVar VariationId is 137369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.526 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.392 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.1929G>A	p.Ala643Ala	synonymous	Exon 12 of 17	NP_001357227.2	F8VWL3
FGD4	NM_001384126.1		c.1929G>A	p.Ala643Ala	synonymous	Exon 12 of 18	NP_001371055.1
FGD4	NM_001304481.2		c.1773G>A	p.Ala591Ala	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.1929G>A	p.Ala643Ala	synonymous	Exon 12 of 17	ENSP00000449273.1	F8VWL3
FGD4	ENST00000395740.5	TSL:1	n.*910G>A		non_coding_transcript_exon	Exon 13 of 17	ENSP00000379089.1	E9PNX0
FGD4	ENST00000395740.5	TSL:1	n.*910G>A		3_prime_UTR	Exon 13 of 17	ENSP00000379089.1	E9PNX0

Frequencies

GnomAD3 genomes

AF:

0.265

AC:

40216

AN:

151530

Hom.:

5636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.472

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.406

Gnomad FIN

AF:

0.225

Gnomad MID

AF:

0.369

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.308

GnomAD2 exomes

AF:

0.286

AC:

70080

AN:

245294

AF XY:

0.299

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.253

Gnomad ASJ exome

AF:

0.373

Gnomad EAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.229

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.299

GnomAD4 exome

AF:

0.292

AC:

419752

AN:

1435932

Hom.:

63767

Cov.:

AF XY:

0.299

AC XY:

213396

AN XY:

714854

show subpopulations

African (AFR)

AF:

0.182

AC:

6008

AN:

33074

American (AMR)

AF:

0.255

AC:

11235

AN:

44122

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

9313

AN:

25702

East Asian (EAS)

AF:

0.164

AC:

6473

AN:

39542

South Asian (SAS)

AF:

0.409

AC:

34744

AN:

85022

European-Finnish (FIN)

AF:

0.234

AC:

12411

AN:

52996

Middle Eastern (MID)

AF:

0.356

AC:

1806

AN:

5066

European-Non Finnish (NFE)

AF:

0.294

AC:

320515

AN:

1091078

Other (OTH)

AF:

0.291

AC:

17247

AN:

59330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

13390

26779

40169

53558

66948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10438

20876

31314

41752

52190

<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:

0.265

AC:

40218

AN:

151626

Hom.:

5638

Cov.:

AF XY:

0.266

AC XY:

19696

AN XY:

74048

show subpopulations

African (AFR)

AF:

0.187

AC:

7713

AN:

41328

American (AMR)

AF:

0.284

AC:

4322

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

1282

AN:

3468

East Asian (EAS)

AF:

0.162

AC:

836

AN:

5156

South Asian (SAS)

AF:

0.407

AC:

1955

AN:

4808

European-Finnish (FIN)

AF:

0.225

AC:

2351

AN:

10426

Middle Eastern (MID)

AF:

0.370

AC:

108

AN:

292

European-Non Finnish (NFE)

AF:

0.303

AC:

20582

AN:

67920

Other (OTH)

AF:

0.305

AC:

641

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1493

2986

4479

5972

7465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

426

852

1278

1704

2130

<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:

0.278

Hom.:

4874

Bravo

AF:

0.263

Asia WGS

AF:

0.281

AC:

979

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 (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

-0.38

CADD

Benign

7.9

(source)

DANN

Benign

0.61

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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