rs7315682

Variant names:

• chr12-32533023-C-T
• rs7315682
• NM_001370298.3:c.167-31114C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001370298.3(FGD4):​c.167-31114C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,094 control chromosomes in the GnomAD database, including 8,138 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (8138 hom., cov: 32)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.142
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.167-31114C>T		intron_variant	Intron 1 of 16	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.167-31114C>T		intron_variant	Intron 1 of 16	5	NM_001370298.3	ENSP00000449273.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39579 AN: 151976 Hom.: 8106 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.217

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

GnomAD4 genome AF: 0.261 AC: 39660 AN: 152094 Hom.: 8138 Cov.: 32 AF XY: 0.257 AC XY: 19081 AN XY: 74334

African (AFR) AF: 0.575 AC: 23824 AN: 41454

American (AMR) AF: 0.141 AC: 2155 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3468

East Asian (EAS) AF: 0.139 AC: 722 AN: 5176

South Asian (SAS) AF: 0.229 AC: 1106 AN: 4820

European-Finnish (FIN) AF: 0.125 AC: 1326 AN: 10580

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9326 AN: 67994

Other (OTH) AF: 0.219 AC: 463 AN: 2114

Alfa AF: 0.178 Hom.: 6013

Bravo AF: 0.275

Asia WGS AF: 0.246 AC: 857 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.23
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs7315682; hg19: chr12-32685957;