dbSNP rs374124835: FGD4:p.Arg16Gln (chr12-32399840-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001370298.3(FGD4):c.47G>A(p.Arg16Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,531,634 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0064 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 8 hom. )

Consequence

FGD4
NM_001370298.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.64

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005855173).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00638 (972/152264) while in subpopulation AFR AF= 0.0221 (919/41566). AF 95% confidence interval is 0.0209. There are 9 homozygotes in gnomad4. There are 475 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FGD4	NM_001370298.3 link	c.47G>A	p.Arg16Gln	missense_variant	Exon 1 of 17	ENST00000534526.7	NP_001357227.2
FGD4	NM_001384126.1 link	c.47G>A	p.Arg16Gln	missense_variant	Exon 1 of 18		NP_001371055.1
FGD4	XR_001748576.2 link	n.283G>A		non_coding_transcript_exon_variant	Exon 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7 link	c.47G>A	p.Arg16Gln	missense_variant	Exon 1 of 17	5	NM_001370298.3	ENSP00000449273.1		F8VWL3
FGD4	ENST00000550091.5 link	n.-16G>A		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00634

AC:

965

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00118

AC:

147

AN:

124712

Hom.:

AF XY:

0.000715

AC XY:

AN XY:

68486

show subpopulations

Gnomad AFR exome

AF:

0.0221

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000897

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000871

Gnomad OTH exome

AF:

0.000259

GnomAD4 exome

AF:

0.000626

AC:

864

AN:

1379370

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

352

AN XY:

680698

show subpopulations

Gnomad4 AFR exome

AF:

0.0224

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000506

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000241

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00638

AC:

972

AN:

152264

Hom.:

Cov.:

AF XY:

0.00638

AC XY:

475

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0221

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.00757

ExAC

AF:

0.000293

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0059

MetaSVM

Benign

-0.49

PROVEAN

Benign

-0.34

REVEL

Benign

0.058

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.33

MutPred

0.43

Gain of catalytic residue at K17 (P = 0.0026);

MVP

0.83

ClinPred

0.086

GERP RS

2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over