rs1995226

Variant names:

• chr12-32616818-C-G
• rs1995226
• NM_001370298.3:c.1750-2880C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32616818-C-G
• chr12-32616818-C-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.1750-2880C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,164 control chromosomes in the GnomAD database, including 928 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 0.10 (928 hom., cov: 33)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

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.1750-2880C>G		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.1750-2880C>G		intron	N/A	NP_001371055.1
	FGD4	NM_001304481.2		c.1594-2880C>G		intron	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.1750-2880C>G		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.*731-2880C>G		intron	N/A	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000531134.7	TSL:2	c.1594-2880C>G		intron	N/A	ENSP00000431323.1	B7Z493

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15882 AN: 152046 Hom.: 924 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0747

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.0653

Gnomad FIN AF: 0.0474

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.104

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

GnomAD4 genome AF: 0.104 AC: 15896 AN: 152164 Hom.: 928 Cov.: 33 AF XY: 0.101 AC XY: 7485 AN XY: 74384

African (AFR) AF: 0.102 AC: 4240 AN: 41484

American (AMR) AF: 0.141 AC: 2150 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 259 AN: 3468

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5186

South Asian (SAS) AF: 0.0668 AC: 323 AN: 4832

European-Finnish (FIN) AF: 0.0474 AC: 502 AN: 10582

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

European-Non Finnish (NFE) AF: 0.118 AC: 8003 AN: 68010

Other (OTH) AF: 0.102 AC: 216 AN: 2112

Alfa AF: 0.108 Hom.: 106

Bravo AF: 0.113

Asia WGS AF: 0.0530 AC: 187 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.36
PhyloP100		-0.22
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: rs1995226; hg19: chr12-32769752;