chr12-32625647-T-C

Position:

chr12-32625647-T-C

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, 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, intron

Scores

Splicing: ADA: 0.00001228

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

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]

FGD4 links:

FGD4 (HGNC:):

FGD4 links:

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	Protein	UniProt
FGD4	NM_001370298.3 linkuse as main transcript	c.2047-7T>C		splice_region_variant, intron_variant		ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7 linkuse as main transcript	c.2047-7T>C		splice_region_variant, intron_variant		5	NM_001370298.3	ENSP00000449273.1		F8VWL3

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

22880

AN:

151946

Hom.:

1989

Cov.:

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.:

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.:

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 12, 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 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. -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over