rs10844253

Positions:

chr12-32611250-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001370298.3(FGD4):c.1716G>A(p.Arg572=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,613,716 control chromosomes in the GnomAD database, including 72,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6102 hom., cov: 33)

Exomes 𝑓: 0.30 ( 66660 hom. )

Consequence

FGD4
NM_001370298.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0900

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 12-32611250-G-A is Benign according to our data. Variant chr12-32611250-G-A is described in ClinVar as [Benign]. Clinvar id is 137368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32611250-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.09 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD4	NM_001370298.3 linkuse as main transcript	c.1716G>A	p.Arg572=	synonymous_variant	10/17	ENST00000534526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD4	ENST00000534526.7 linkuse as main transcript	c.1716G>A	p.Arg572=	synonymous_variant	10/17	5	NM_001370298.3

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42310

AN:

151944

Hom.:

6093

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.294

Gnomad ASJ

AF:

0.369

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.405

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.316

GnomAD3 exomes

AF:

0.293

AC:

73790

AN:

251448

Hom.:

11433

AF XY:

0.306

AC XY:

41532

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.231

Gnomad AMR exome

AF:

0.259

Gnomad ASJ exome

AF:

0.375

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.412

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.307

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.298

AC:

435984

AN:

1461654

Hom.:

66660

Cov.:

AF XY:

0.304

AC XY:

221089

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.234

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.366

Gnomad4 EAS exome

AF:

0.163

Gnomad4 SAS exome

AF:

0.411

Gnomad4 FIN exome

AF:

0.236

Gnomad4 NFE exome

AF:

0.299

Gnomad4 OTH exome

AF:

0.298

GnomAD4 genome

AF:

0.278

AC:

42342

AN:

152062

Hom.:

6102

Cov.:

AF XY:

0.279

AC XY:

20724

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.232

Gnomad4 AMR

AF:

0.293

Gnomad4 ASJ

AF:

0.369

Gnomad4 EAS

AF:

0.160

Gnomad4 SAS

AF:

0.406

Gnomad4 FIN

AF:

0.223

Gnomad4 NFE

AF:

0.303

Gnomad4 OTH

AF:

0.317

Alfa

AF:

0.305

Hom.:

9667

Bravo

AF:

0.279

Asia WGS

AF:

0.294

AC:

1024

AN:

3478

EpiCase

AF:

0.314

EpiControl

AF:

0.326

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease type 4H

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.3

DANN

Benign

0.57

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