rs12823621

Positions:

• chr12-32602325-G-A

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.1404+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,613,464 control chromosomes in the GnomAD database, including 7,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (677 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7081 hom.)
• Consequence: FGD4 NM_001370298.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001027
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.46

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=-0.81).
• BP6: Variant 12-32602325-G-A is Benign according to our data. Variant chr12-32602325-G-A is described in ClinVar as [Benign]. Clinvar id is 308292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32602325-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD4	NM_001370298.3	c.1404+8G>A		splice_region_variant, intron_variant		ENST00000534526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD4	ENST00000534526.7	c.1404+8G>A		splice_region_variant, intron_variant		5	NM_001370298.3

Frequencies

GnomAD3 genomes AF: 0.0757 AC: 11511 AN: 152038 Hom.: 677 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0742

GnomAD3 exomes AF: 0.0784 AC: 19703 AN: 251360 Hom.: 1123 AF XY: 0.0794 AC XY: 10782 AN XY: 135868

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0245

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0816

GnomAD4 exome AF: 0.0923 AC: 134878 AN: 1461308 Hom.: 7081 Cov.: 33 AF XY: 0.0910 AC XY: 66166 AN XY: 726988

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0433

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0256

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0859

GnomAD4 genome AF: 0.0756 AC: 11505 AN: 152156 Hom.: 677 Cov.: 32 AF XY: 0.0749 AC XY: 5570 AN XY: 74360

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.0674

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0735

Alfa AF: 0.100 Hom.: 1385

Bravo AF: 0.0670

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 02, 2017

- -

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 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

Mar 03, 2015

- -

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	-0.81
CADD	Benign	7.9
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0
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: rs12823621; hg19: chr12-32755259;