12-32640446-T-A

Variant names:

• chr12-32640446-T-A
• NM_001370298.3:c.2625T>A
• FGD4 p.Ala875Ala

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001370298.3(FGD4):​c.2625T>A​(p.Ala875Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A875A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGD4 NM_001370298.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370298.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD4	NM_001370298.3	MANE Select	c.2625T>A	p.Ala875Ala	synonymous	Exon 17 of 17	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.2625T>A	p.Ala875Ala	synonymous	Exon 17 of 18	NP_001371055.1
	FGD4	NM_001304481.2		c.2469T>A	p.Ala823Ala	synonymous	Exon 17 of 17	NP_001291410.1	B7Z493

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD4	ENST00000534526.7	TSL:5 MANE Select	c.2625T>A	p.Ala875Ala	synonymous	Exon 17 of 17	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000531134.7	TSL:2	c.2469T>A	p.Ala823Ala	synonymous	Exon 17 of 17	ENSP00000431323.1	B7Z493
	FGD4	ENST00000427716.7	TSL:2	c.2214T>A	p.Ala738Ala	synonymous	Exon 18 of 18	ENSP00000394487.2	Q96M96-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.5
DANN	Benign	0.72
PhyloP100		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-32793380;