12-32564054-T-A

Position:

• chr12-32564054-T-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD4	NM_001370298.3	c.167-83T>A		intron_variant		ENST00000534526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD4	ENST00000534526.7	c.167-83T>A		intron_variant		5	NM_001370298.3

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

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.296

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.0681

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.214

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

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.0661

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.0829

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.217

Alfa AF: 0.0462 Hom.: 36

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs61926167; hg19: chr12-32716988;