12-32486135-TG-TGG

Variant names:

• chr12-32486135-T-TG
• rs1357153004
• NM_001370298.3:c.167-77996dupG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001304481.2(FGD4):​c.8dupG​(p.Cys4LeufsTer25) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000145 in 1,377,062 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FGD4 NM_001304481.2 frameshift, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 49 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304481.2. 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.167-77996dupG		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001304481.2		c.8dupG	p.Cys4LeufsTer25	frameshift splice_region	Exon 1 of 17	NP_001291410.1	B7Z493
	FGD4	NM_001330374.2		c.-343dupG		splice_region	Exon 1 of 16	NP_001317303.1	F8W1R0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD4	ENST00000534526.7	TSL:5 MANE Select	c.167-77996dupG		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000531134.7	TSL:2	c.8dupG	p.Cys4LeufsTer25	frameshift splice_region	Exon 1 of 17	ENSP00000431323.1	B7Z493
	FGD4	ENST00000550091.5	TSL:4	n.105-77996dupG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 120614 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1377062 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 679350

African (AFR) AF: 0.00 AC: 0 AN: 31274

American (AMR) AF: 0.00 AC: 0 AN: 34256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25018

East Asian (EAS) AF: 0.00 AC: 0 AN: 35494

South Asian (SAS) AF: 0.00 AC: 0 AN: 77672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076668

Other (OTH) AF: 0.00 AC: 0 AN: 57622

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

Splicing

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

Other links and lift over

dbSNP: rs1357153004; hg19: chr12-32639069;