12-32534418-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001385118.1(FGD4):c.-326A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,518,204 control chromosomes in the GnomAD database, including 641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.021 ( 72 hom., cov: 32)

Exomes 𝑓: 0.023 ( 569 hom. )

Consequence

FGD4
NM_001385118.1 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:4

Conservation

PhyloP100: -0.541

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014554858).

BP6

Variant 12-32534418-A-G is Benign according to our data. Variant chr12-32534418-A-G is described in ClinVar as [Benign]. Clinvar id is 1284800.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-32534418-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3 link	c.167-29719A>G		intron_variant	Intron 1 of 16	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7 link	c.167-29719A>G		intron_variant	Intron 1 of 16	5	NM_001370298.3	ENSP00000449273.1		F8VWL3

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3199

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.0417

Gnomad SAS

AF:

0.0741

Gnomad FIN

AF:

0.0622

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0276

AC:

3353

AN:

121474

Hom.:

AF XY:

0.0304

AC XY:

2031

AN XY:

66748

show subpopulations

Gnomad AFR exome

AF:

0.0114

Gnomad AMR exome

AF:

0.00852

Gnomad ASJ exome

AF:

0.00575

Gnomad EAS exome

AF:

0.0442

Gnomad SAS exome

AF:

0.0702

Gnomad FIN exome

AF:

0.0444

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.0203

GnomAD4 exome

AF:

0.0228

AC:

31084

AN:

1365862

Hom.:

569

Cov.:

AF XY:

0.0242

AC XY:

16323

AN XY:

674188

show subpopulations

Gnomad4 AFR exome

AF:

0.0127

Gnomad4 AMR exome

AF:

0.00804

Gnomad4 ASJ exome

AF:

0.00659

Gnomad4 EAS exome

AF:

0.0317

Gnomad4 SAS exome

AF:

0.0729

Gnomad4 FIN exome

AF:

0.0416

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0241

GnomAD4 genome

AF:

0.0210

AC:

3194

AN:

152342

Hom.:

Cov.:

AF XY:

0.0237

AC XY:

1766

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0120

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.0418

Gnomad4 SAS

AF:

0.0737

Gnomad4 FIN

AF:

0.0622

Gnomad4 NFE

AF:

0.0175

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0157

Hom.:

Bravo

AF:

0.0155

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0228

AC:

ExAC

AF:

0.0415

AC:

620

Asia WGS

AF:

0.0680

AC:

236

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

FGD4-related disorder

Benign:1

Mar 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.8

DANN

Benign

0.97

DEOGEN2

Benign

0.010

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0088

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.98

PROVEAN

Benign

0.12

REVEL

Benign

0.11

Sift

Benign

0.24

Polyphen

0.0

Vest4

0.016

ClinPred

0.0016

GERP RS

-2.5

gMVP

0.072

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over