12-32582406-A-T

Variant names:

• chr12-32582406-A-T
• rs1452437045
• NM_001370298.3:c.950A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001370298.3(FGD4):​c.950A>T​(p.Glu317Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E317K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGD4 NM_001370298.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.69
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4H

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1983662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.950A>T	p.Glu317Val	missense_variant	Exon 4 of 17	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.950A>T	p.Glu317Val	missense_variant	Exon 4 of 17	5	NM_001370298.3	ENSP00000449273.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	2.0	.;.;.;M;.;.
PhyloP100		5.7
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.046	D;T;D;D;T;T
Polyphen		0.45, 0.60, 0.80	.;P;P;P;.;P
Vest4		0.25
MutPred		0.36		.;.;.;.;.;Loss of methylation at K289 (P = 0.1374);
MVP		0.83
MPC		0.45
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.45
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs1452437045; hg19: chr12-32735340;