12-32502151-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370298.3(FGD4):c.167-61986C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 985,422 control chromosomes in the GnomAD database, including 2,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (273 hom., cov: 33)
  • Exomes 𝑓: 0.074 (2392 hom.)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0700

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-32502151-C-T is Benign according to our data. Variant chr12-32502151-C-T is described in ClinVar as [Benign]. Clinvar id is 308277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD4	NM_001370298.3	c.167-61986C>T		intron_variant		ENST00000534526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD4	ENST00000534526.7	c.167-61986C>T		intron_variant		5	NM_001370298.3

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7729 AN: 152132 Hom.: 273 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.0518

Gnomad EAS AF: 0.00461

Gnomad SAS AF: 0.0988

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.0556

GnomAD4 exome AF: 0.0744 AC: 62017 AN: 833172 Hom.: 2392 Cov.: 30 AF XY: 0.0751 AC XY: 28896 AN XY: 384764

Gnomad4 AFR exome AF: 0.00861

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.0537

Gnomad4 EAS exome AF: 0.00386

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.0324

Gnomad4 NFE exome AF: 0.0757

Gnomad4 OTH exome AF: 0.0717

GnomAD4 genome AF: 0.0507 AC: 7726 AN: 152250 Hom.: 273 Cov.: 33 AF XY: 0.0490 AC XY: 3649 AN XY: 74444

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.0508

Gnomad4 ASJ AF: 0.0518

Gnomad4 EAS AF: 0.00462

Gnomad4 SAS AF: 0.0990

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0738

Gnomad4 OTH AF: 0.0545

Alfa AF: 0.0727 Hom.: 459

Bravo AF: 0.0506

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4H Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	13
Dann	Benign	0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11052033; hg19: chr12-32655085;