rs11052110

chr12-32624428-G-Achr12-32624428-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. A643A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5638 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63767 hom.)
• Consequence: FGD4 NM_001370298.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.526

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]

ACMG classification

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	UniProt
FGD4	NM_001370298.3	c.1929G>A	p.Ala643=	synonymous_variant	12/17	ENST00000534526.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40216 AN: 151530 Hom.: 5636 Cov.: 32

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

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.: 30 AF XY: 0.299 AC XY: 213396 AN XY: 714854

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.: 32 AF XY: 0.266 AC XY: 19696 AN XY: 74048

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:8

Revision: criteria provided, multiple submitters, no conflicts

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	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	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other links and lift over

dbSNP: rs11052110; hg19: chr12-32777362; COSMIC: COSV56783876;