rs11052110

Positions:

Variant summary

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

The NM_001370298.3(FGD4):c.1929G>A(p.Ala643=) 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 (★★).

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

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=-0.38).

BP6

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGD4	NM_001370298.3 linkuse as main transcript	c.1929G>A	p.Ala643=	synonymous_variant	12/17	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7 linkuse as main transcript	c.1929G>A	p.Ala643=	synonymous_variant	12/17	5	NM_001370298.3	ENSP00000449273

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

GnomAD3 exomes

AF:

0.286

AC:

70080

AN:

245294

Hom.:

10601

AF XY:

0.299

AC XY:

39624

AN XY:

132598

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 SAS exome

AF:

0.409

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

Gnomad4 AFR exome

AF:

0.182

Gnomad4 AMR exome

AF:

0.255

Gnomad4 ASJ exome

AF:

0.362

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.409

Gnomad4 FIN exome

AF:

0.234

Gnomad4 NFE exome

AF:

0.294

Gnomad4 OTH exome

AF:

0.291

GnomAD4 genome

AF:

0.265

AC:

40218

AN:

151626

Hom.:

5638

Cov.:

AF XY:

0.266

AC XY:

19696

AN XY:

74048

show subpopulations

Gnomad4 AFR

AF:

0.187

Gnomad4 AMR

AF:

0.284

Gnomad4 ASJ

AF:

0.370

Gnomad4 EAS

AF:

0.162

Gnomad4 SAS

AF:

0.407

Gnomad4 FIN

AF:

0.225

Gnomad4 NFE

AF:

0.303

Gnomad4 OTH

AF:

0.305

Alfa

AF:

0.277

Hom.:

4374

Bravo

AF:

0.263

Asia WGS

AF:

0.281

AC:

979

AN:

3478

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, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease type 4H

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

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

-0.38

CADD

Benign

7.9

DANN

Benign

0.61

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