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rs11052113

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001370298.3(FGD4):c.2047-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,064 control chromosomes in the GnomAD database, including 16,562 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 0.15 ( 1998 hom., cov: 31)
Exomes 𝑓: 0.14 ( 14564 hom. )

Consequence

FGD4
NM_001370298.3 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00001228
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.674
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 12-32625647-T-C is Benign according to our data. Variant chr12-32625647-T-C is described in ClinVar as [Benign]. Clinvar id is 308299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32625647-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FGD4NM_001370298.3 linkuse as main transcriptc.2047-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000534526.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGD4ENST00000534526.7 linkuse as main transcriptc.2047-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 5 NM_001370298.3

Frequencies

GnomAD3 genomes
AF:
0.151
AC:
22880
AN:
151946
Hom.:
1989
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.226
Gnomad AMI
AF:
0.0967
Gnomad AMR
AF:
0.165
Gnomad ASJ
AF:
0.0954
Gnomad EAS
AF:
0.0131
Gnomad SAS
AF:
0.120
Gnomad FIN
AF:
0.0550
Gnomad MID
AF:
0.259
Gnomad NFE
AF:
0.133
Gnomad OTH
AF:
0.147
GnomAD3 exomes
AF:
0.131
AC:
33023
AN:
251208
Hom.:
2631
AF XY:
0.127
AC XY:
17246
AN XY:
135820
show subpopulations
Gnomad AFR exome
AF:
0.224
Gnomad AMR exome
AF:
0.221
Gnomad ASJ exome
AF:
0.0981
Gnomad EAS exome
AF:
0.0107
Gnomad SAS exome
AF:
0.131
Gnomad FIN exome
AF:
0.0582
Gnomad NFE exome
AF:
0.127
Gnomad OTH exome
AF:
0.140
GnomAD4 exome
AF:
0.135
AC:
197816
AN:
1461000
Hom.:
14564
Cov.:
32
AF XY:
0.134
AC XY:
97396
AN XY:
726848
show subpopulations
Gnomad4 AFR exome
AF:
0.233
Gnomad4 AMR exome
AF:
0.216
Gnomad4 ASJ exome
AF:
0.101
Gnomad4 EAS exome
AF:
0.0121
Gnomad4 SAS exome
AF:
0.131
Gnomad4 FIN exome
AF:
0.0609
Gnomad4 NFE exome
AF:
0.138
Gnomad4 OTH exome
AF:
0.140
GnomAD4 genome
AF:
0.151
AC:
22915
AN:
152064
Hom.:
1998
Cov.:
31
AF XY:
0.146
AC XY:
10869
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.225
Gnomad4 AMR
AF:
0.165
Gnomad4 ASJ
AF:
0.0954
Gnomad4 EAS
AF:
0.0131
Gnomad4 SAS
AF:
0.121
Gnomad4 FIN
AF:
0.0550
Gnomad4 NFE
AF:
0.133
Gnomad4 OTH
AF:
0.149
Alfa
AF:
0.138
Hom.:
807
Bravo
AF:
0.164
Asia WGS
AF:
0.103
AC:
360
AN:
3478
EpiCase
AF:
0.141
EpiControl
AF:
0.134

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJul 12, 2017- -
Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -
Charcot-Marie-Tooth disease type 4H Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingGeneDxMar 03, 2015- -
Charcot-Marie-Tooth disease type 4 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
Cadd
Benign
2.1
Dann
Benign
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000012
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11052113; hg19: chr12-32778581; API