12-32564054-T-A

Variant names:

• chr12-32564054-T-A
• rs61926167
• NM_001370298.3:c.167-83T>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.167-83T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,199,558 control chromosomes in the GnomAD database, including 25,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3324 hom., cov: 25)
  • Exomes 𝑓: 0.20 (21793 hom.)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.895
• Publications: 3 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=-0.82).
• BP6: Variant 12-32564054-T-A is Benign according to our data. Variant chr12-32564054-T-A is described in ClinVar as Benign. ClinVar VariationId is 1183592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 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.167-83T>A		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.167-83T>A		intron	N/A	NP_001371055.1
	FGD4	NM_001304481.2		c.11-83T>A		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.167-83T>A		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.-245-83T>A		intron	N/A	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000494275.5	TSL:1	n.291-83T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.216 AC: 28644 AN: 132528 Hom.: 3314 Cov.: 25

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.0657

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0829

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.202 AC: 215807 AN: 1066956 Hom.: 21793 AF XY: 0.202 AC XY: 105559 AN XY: 522000

African (AFR) AF: 0.319 AC: 7003 AN: 21964

American (AMR) AF: 0.296 AC: 6837 AN: 23102

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 3867 AN: 17532

East Asian (EAS) AF: 0.0681 AC: 1971 AN: 28928

South Asian (SAS) AF: 0.203 AC: 10208 AN: 50360

European-Finnish (FIN) AF: 0.107 AC: 2956 AN: 27650

Middle Eastern (MID) AF: 0.273 AC: 966 AN: 3540

European-Non Finnish (NFE) AF: 0.203 AC: 172291 AN: 848522

Other (OTH) AF: 0.214 AC: 9708 AN: 45358

GnomAD4 genome AF: 0.216 AC: 28684 AN: 132602 Hom.: 3324 Cov.: 25 AF XY: 0.211 AC XY: 13524 AN XY: 64054

African (AFR) AF: 0.311 AC: 10247 AN: 32926

American (AMR) AF: 0.243 AC: 3186 AN: 13088

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 688 AN: 3250

East Asian (EAS) AF: 0.0661 AC: 299 AN: 4524

South Asian (SAS) AF: 0.168 AC: 686 AN: 4072

European-Finnish (FIN) AF: 0.0829 AC: 717 AN: 8646

Middle Eastern (MID) AF: 0.304 AC: 82 AN: 270

European-Non Finnish (NFE) AF: 0.193 AC: 12199 AN: 63152

Other (OTH) AF: 0.217 AC: 392 AN: 1804

Alfa AF: 0.0462 Hom.: 36

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.21
PhyloP100		-0.90
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: rs61926167; hg19: chr12-32716988;