rs10844253

chr12-32611250-G-A

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0900

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=-0.45).
• 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	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	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.: 33

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

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.: 37 AF XY: 0.304 AC XY: 221089 AN XY: 727142

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.: 33 AF XY: 0.279 AC XY: 20724 AN XY: 74332

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -

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	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, 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	-0.45
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

Other links and lift over

dbSNP: rs10844253; hg19: chr12-32764184; COSMIC: COSV56781438;