12-32582302-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001370298.3(FGD4):c.846C>T(p.Asp282Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,613,920 control chromosomes in the GnomAD database, including 135,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 18375 hom., cov: 33)

Exomes 𝑓: 0.40 ( 117291 hom. )

Consequence

FGD4
NM_001370298.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.847

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 12-32582302-C-T is Benign according to our data. Variant chr12-32582302-C-T is described in ClinVar as [Benign]. Clinvar id is 308287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32582302-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.847 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3 link	c.846C>T	p.Asp282Asp	synonymous_variant	Exon 4 of 17	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7 link	c.846C>T	p.Asp282Asp	synonymous_variant	Exon 4 of 17	5	NM_001370298.3	ENSP00000449273.1		F8VWL3

Frequencies

GnomAD3 genomes

AF:

0.472

AC:

71661

AN:

151970

Hom.:

18352

Cov.:

show subpopulations

Gnomad AFR

AF:

0.682

Gnomad AMI

AF:

0.516

Gnomad AMR

AF:

0.510

Gnomad ASJ

AF:

0.423

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.469

GnomAD3 exomes

AF:

0.411

AC:

103295

AN:

251402

Hom.:

22590

AF XY:

0.406

AC XY:

55148

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.686

Gnomad AMR exome

AF:

0.509

Gnomad ASJ exome

AF:

0.436

Gnomad EAS exome

AF:

0.226

Gnomad SAS exome

AF:

0.420

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.382

Gnomad OTH exome

AF:

0.426

GnomAD4 exome

AF:

0.395

AC:

577859

AN:

1461832

Hom.:

117291

Cov.:

AF XY:

0.396

AC XY:

287725

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.695

Gnomad4 AMR exome

AF:

0.509

Gnomad4 ASJ exome

AF:

0.432

Gnomad4 EAS exome

AF:

0.212

Gnomad4 SAS exome

AF:

0.419

Gnomad4 FIN exome

AF:

0.332

Gnomad4 NFE exome

AF:

0.387

Gnomad4 OTH exome

AF:

0.411

GnomAD4 genome

AF:

0.472

AC:

71745

AN:

152088

Hom.:

18375

Cov.:

AF XY:

0.469

AC XY:

34831

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.682

Gnomad4 AMR

AF:

0.510

Gnomad4 ASJ

AF:

0.423

Gnomad4 EAS

AF:

0.222

Gnomad4 SAS

AF:

0.402

Gnomad4 FIN

AF:

0.328

Gnomad4 NFE

AF:

0.383

Gnomad4 OTH

AF:

0.467

Alfa

AF:

0.393

Hom.:

20180

Bravo

AF:

0.499

EpiCase

AF:

0.400

EpiControl

AF:

0.403

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4H

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.20

DANN

Benign

0.25

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