rs1995227

Variant names:

• chr12-32616698-C-G
• rs1995227
• NM_001370298.3:c.1750-3000C>G

Variant summary

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

The NM_001370298.3(FGD4):​c.1750-3000C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.083 in 152,262 control chromosomes in the GnomAD database, including 698 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 0.083 (698 hom., cov: 33)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.147
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.1750-3000C>G		intron_variant	Intron 10 of 16	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.1750-3000C>G		intron_variant	Intron 10 of 16	5	NM_001370298.3	ENSP00000449273.1

Frequencies

GnomAD3 genomes AF: 0.0830 AC: 12628 AN: 152144 Hom.: 697 Cov.: 33

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.0652

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0922

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

GnomAD4 genome AF: 0.0830 AC: 12631 AN: 152262 Hom.: 698 Cov.: 33 AF XY: 0.0795 AC XY: 5915 AN XY: 74440

African (AFR) AF: 0.0268 AC: 1114 AN: 41548

American (AMR) AF: 0.133 AC: 2029 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 269 AN: 3472

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5188

South Asian (SAS) AF: 0.0667 AC: 322 AN: 4826

European-Finnish (FIN) AF: 0.0473 AC: 501 AN: 10592

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8000 AN: 68012

Other (OTH) AF: 0.0907 AC: 192 AN: 2116

Alfa AF: 0.0946 Hom.: 94

Bravo AF: 0.0891

Asia WGS AF: 0.0470 AC: 166 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.57
PhyloP100		0.15
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: rs1995227; hg19: chr12-32769632;