12-32610778-TCA-GCC

Variant names:

• chr12-32610778-TCA-GCC
• NM_001370298.3:c.1546_1548delTCAinsGCC
• FGD4 p.Ser516Ala

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001370298.3(FGD4):​c.1546_1548delTCAinsGCC​(p.Ser516Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S516S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGD4 NM_001370298.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69
• 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 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1546_1548delTCAinsGCC	p.Ser516Ala	missense splice_region	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.1546_1548delTCAinsGCC	p.Ser516Ala	missense splice_region	N/A	NP_001371055.1
	FGD4	NM_001304481.2		c.1390_1392delTCAinsGCC	p.Ser464Ala	missense splice_region	N/A	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.1546_1548delTCAinsGCC	p.Ser516Ala	missense splice_region	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.*527_*529delTCAinsGCC		splice_region non_coding_transcript_exon	Exon 10 of 17	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000395740.5	TSL:1	n.*527_*529delTCAinsGCC		3_prime_UTR	Exon 10 of 17	ENSP00000379089.1	E9PNX0

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

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: chr12-32763712;