12-32502151-C-T

Variant names:

• chr12-32502151-C-T
• rs11052033
• NM_001370298.3:c.167-61986C>T

Variant summary

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

The NM_139241.3(FGD4):​c.-433C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 985,422 control chromosomes in the GnomAD database, including 2,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (273 hom., cov: 33)
  • Exomes 𝑓: 0.074 (2392 hom.)
• Consequence: FGD4 NM_139241.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0700
• Publications: 4 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=-0.59).
• BP6: Variant 12-32502151-C-T is Benign according to our data. Variant chr12-32502151-C-T is described in ClinVar as Benign. ClinVar VariationId is 308277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139241.3. 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.167-61986C>T		intron	N/A	NP_001357227.2	F8VWL3
	FGD4	NM_139241.3		c.-433C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_640334.2	Q96M96-1
	FGD4	NM_139241.3		c.-433C>T		5_prime_UTR	Exon 1 of 17	NP_640334.2	Q96M96-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD4	ENST00000534526.7	TSL:5 MANE Select	c.167-61986C>T		intron	N/A	ENSP00000449273.1	F8VWL3
	FGD4	ENST00000494275.5	TSL:1	n.103C>T		non_coding_transcript_exon	Exon 1 of 3
	FGD4	ENST00000682739.1		c.-1205C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	ENSP00000507616.1	F8W1R0

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7729 AN: 152132 Hom.: 273 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.0518

Gnomad EAS AF: 0.00461

Gnomad SAS AF: 0.0988

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.0556

GnomAD4 exome AF: 0.0744 AC: 62017 AN: 833172 Hom.: 2392 Cov.: 30 AF XY: 0.0751 AC XY: 28896 AN XY: 384764

African (AFR) AF: 0.00861 AC: 136 AN: 15790

American (AMR) AF: 0.0508 AC: 50 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.0537 AC: 277 AN: 5154

East Asian (EAS) AF: 0.00386 AC: 14 AN: 3630

South Asian (SAS) AF: 0.105 AC: 1730 AN: 16460

European-Finnish (FIN) AF: 0.0324 AC: 9 AN: 278

Middle Eastern (MID) AF: 0.0969 AC: 157 AN: 1620

European-Non Finnish (NFE) AF: 0.0757 AC: 57687 AN: 761956

Other (OTH) AF: 0.0717 AC: 1957 AN: 27300

GnomAD4 genome AF: 0.0507 AC: 7726 AN: 152250 Hom.: 273 Cov.: 33 AF XY: 0.0490 AC XY: 3649 AN XY: 74444

African (AFR) AF: 0.0143 AC: 594 AN: 41542

American (AMR) AF: 0.0508 AC: 776 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 180 AN: 3472

East Asian (EAS) AF: 0.00462 AC: 24 AN: 5190

South Asian (SAS) AF: 0.0990 AC: 478 AN: 4826

European-Finnish (FIN) AF: 0.0350 AC: 371 AN: 10598

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0738 AC: 5017 AN: 68018

Other (OTH) AF: 0.0545 AC: 115 AN: 2110

Alfa AF: 0.0699 Hom.: 552

Bravo AF: 0.0506

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		0.070
PromoterAI		-0.044	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11052033; hg19: chr12-32655085;