rs12823621

Variant names:

• chr12-32602325-G-A
• rs12823621
• NM_001370298.3:c.1404+8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370298.3(FGD4):​c.1404+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,613,464 control chromosomes in the GnomAD database, including 7,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (677 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7081 hom.)
• Consequence: FGD4 NM_001370298.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001027
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.46
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-32602325-G-A is Benign according to our data. Variant chr12-32602325-G-A is described in ClinVar as Benign. ClinVar VariationId is 308292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 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.1404+8G>A		splice_region intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.1404+8G>A		splice_region intron	N/A	NP_001371055.1
	FGD4	NM_001304481.2		c.1248+8G>A		splice_region 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.1404+8G>A		splice_region intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.*385+8G>A		splice_region intron	N/A	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000531134.7	TSL:2	c.1248+8G>A		splice_region intron	N/A	ENSP00000431323.1	B7Z493

Frequencies

GnomAD3 genomes AF: 0.0757 AC: 11511 AN: 152038 Hom.: 677 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0742

GnomAD2 exomes AF: 0.0784 AC: 19703 AN: 251360 AF XY: 0.0794

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0816

GnomAD4 exome AF: 0.0923 AC: 134878 AN: 1461308 Hom.: 7081 Cov.: 33 AF XY: 0.0910 AC XY: 66166 AN XY: 726988

African (AFR) AF: 0.0129 AC: 433 AN: 33470

American (AMR) AF: 0.0433 AC: 1937 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2837 AN: 26126

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39650

South Asian (SAS) AF: 0.0256 AC: 2204 AN: 86238

European-Finnish (FIN) AF: 0.154 AC: 8239 AN: 53406

Middle Eastern (MID) AF: 0.0453 AC: 261 AN: 5766

European-Non Finnish (NFE) AF: 0.102 AC: 113773 AN: 1111556

Other (OTH) AF: 0.0859 AC: 5187 AN: 60372

GnomAD4 genome AF: 0.0756 AC: 11505 AN: 152156 Hom.: 677 Cov.: 32 AF XY: 0.0749 AC XY: 5570 AN XY: 74360

African (AFR) AF: 0.0160 AC: 663 AN: 41532

American (AMR) AF: 0.0674 AC: 1030 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 401 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4820

European-Finnish (FIN) AF: 0.149 AC: 1579 AN: 10572

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7454 AN: 67998

Other (OTH) AF: 0.0735 AC: 155 AN: 2110

Alfa AF: 0.0940 Hom.: 1643

Bravo AF: 0.0670

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4H (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.34
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0
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: rs12823621; hg19: chr12-32755259;