12-32582302-C-T

Variant names:

• chr12-32582302-C-T
• rs904582
• NM_001370298.3:c.846C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001370298.3(FGD4):​c.846C>T​(p.Asp282Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,613,920 control chromosomes in the GnomAD database, including 135,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18375 hom., cov: 33)
  • Exomes 𝑓: 0.40 (117291 hom.)
• Consequence: FGD4 NM_001370298.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.847
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-32582302-C-T is Benign according to our data. Variant chr12-32582302-C-T is described in ClinVar as Benign. ClinVar VariationId is 308287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.847 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 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.846C>T	p.Asp282Asp	synonymous	Exon 4 of 17	NP_001357227.2	F8VWL3
	FGD4	NM_001384126.1		c.846C>T	p.Asp282Asp	synonymous	Exon 4 of 18	NP_001371055.1
	FGD4	NM_001304481.2		c.690C>T	p.Asp230Asp	synonymous	Exon 4 of 17	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.846C>T	p.Asp282Asp	synonymous	Exon 4 of 17	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000395740.5	TSL:1	n.435C>T		non_coding_transcript_exon	Exon 4 of 17	ENSP00000379089.1	E9PNX0
	FGD4	ENST00000494275.5	TSL:1	n.786C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71661 AN: 151970 Hom.: 18352 Cov.: 33

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.469

GnomAD2 exomes AF: 0.411 AC: 103295 AN: 251402 AF XY: 0.406

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.395 AC: 577859 AN: 1461832 Hom.: 117291 Cov.: 62 AF XY: 0.396 AC XY: 287725 AN XY: 727210

African (AFR) AF: 0.695 AC: 23274 AN: 33480

American (AMR) AF: 0.509 AC: 22751 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 11283 AN: 26136

East Asian (EAS) AF: 0.212 AC: 8412 AN: 39700

South Asian (SAS) AF: 0.419 AC: 36162 AN: 86258

European-Finnish (FIN) AF: 0.332 AC: 17723 AN: 53418

Middle Eastern (MID) AF: 0.531 AC: 3062 AN: 5768

European-Non Finnish (NFE) AF: 0.387 AC: 430387 AN: 1111952

Other (OTH) AF: 0.411 AC: 24805 AN: 60396

GnomAD4 genome AF: 0.472 AC: 71745 AN: 152088 Hom.: 18375 Cov.: 33 AF XY: 0.469 AC XY: 34831 AN XY: 74342

African (AFR) AF: 0.682 AC: 28293 AN: 41484

American (AMR) AF: 0.510 AC: 7793 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1467 AN: 3470

East Asian (EAS) AF: 0.222 AC: 1146 AN: 5172

South Asian (SAS) AF: 0.402 AC: 1940 AN: 4820

European-Finnish (FIN) AF: 0.328 AC: 3465 AN: 10568

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26006 AN: 67972

Other (OTH) AF: 0.467 AC: 989 AN: 2116

Alfa AF: 0.417 Hom.: 37813

Bravo AF: 0.499

EpiCase AF: 0.400

EpiControl AF: 0.403

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.25
PhyloP100		-0.85
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: rs904582; hg19: chr12-32735236; COSMIC: COSV56781591; COSMIC: COSV56781591;