rs281865064

Variant names:

• chr12-32625716-G-A
• rs281865064
• NM_001370298.3:c.2109G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-32625716-G-A
• chr12-32625716-G-N

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001370298.3(FGD4):​c.2109G>A​(p.Met703Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGD4 NM_001370298.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 9.25
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

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.2109G>A	p.Met703Ile	missense	Exon 14 of 17	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.2109G>A	p.Met703Ile	missense	Exon 14 of 18	NP_001371055.1
	FGD4	NM_001304481.2		c.1953G>A	p.Met651Ile	missense	Exon 14 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.2109G>A	p.Met703Ile	missense	Exon 14 of 17	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.*1090G>A		non_coding_transcript_exon	Exon 15 of 17	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000395740.5	TSL:1	n.*1090G>A		3_prime_UTR	Exon 15 of 17	ENSP00000379089.1	E9PNX0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease (1)
-	1	-	Charcot-Marie-Tooth disease type 4H (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.90	P
Vest4		0.94
MutPred		0.59		Gain of methylation at K679 (P = 0.024)
MVP		0.81
MPC		0.92
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.81
Mutation Taster		=10/90	disease causing

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: rs281865064; hg19: chr12-32778650;