12-32534418-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001370298.3(FGD4):c.167-29719A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,518,204 control chromosomes in the GnomAD database, including 641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (72 hom., cov: 32)
  • Exomes 𝑓: 0.023 (569 hom.)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.541

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014554858).
• BP6: Variant 12-32534418-A-G is Benign according to our data. Variant chr12-32534418-A-G is described in ClinVar as [Benign]. Clinvar id is 1284800.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-32534418-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD4	NM_001370298.3	c.167-29719A>G		intron_variant		ENST00000534526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD4	ENST00000534526.7	c.167-29719A>G		intron_variant		5	NM_001370298.3

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3199 AN: 152224 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.0417

Gnomad SAS AF: 0.0741

Gnomad FIN AF: 0.0622

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0276 AC: 3353 AN: 121474 Hom.: 91 AF XY: 0.0304 AC XY: 2031 AN XY: 66748

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.00852

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.0442

Gnomad SAS exome AF: 0.0702

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0228 AC: 31084 AN: 1365862 Hom.: 569 Cov.: 29 AF XY: 0.0242 AC XY: 16323 AN XY: 674188

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.00804

Gnomad4 ASJ exome AF: 0.00659

Gnomad4 EAS exome AF: 0.0317

Gnomad4 SAS exome AF: 0.0729

Gnomad4 FIN exome AF: 0.0416

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0210 AC: 3194 AN: 152342 Hom.: 72 Cov.: 32 AF XY: 0.0237 AC XY: 1766 AN XY: 74488

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.0418

Gnomad4 SAS AF: 0.0737

Gnomad4 FIN AF: 0.0622

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0157 Hom.: 5

Bravo AF: 0.0155

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0228 AC: 88

ExAC AF: 0.0415 AC: 620

Asia WGS AF: 0.0680 AC: 236 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

FGD4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	8.8
Dann	Benign	0.97
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	0.12	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.016
ClinPred		0.0016	T
GERP RS		-2.5
gMVP		0.072

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: rs17537634; hg19: chr12-32687352;