rs10844258

Positions:

• chr12-32615902-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001370298.3(FGD4):​c.1750-3796G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 151,734 control chromosomes in the GnomAD database, including 18,186 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (18186 hom., cov: 31)
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD4	NM_001370298.3	c.1750-3796G>A		intron_variant		ENST00000534526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD4	ENST00000534526.7	c.1750-3796G>A		intron_variant		5	NM_001370298.3

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72821 AN: 151616 Hom.: 18162 Cov.: 31

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.500

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.480 AC: 72882 AN: 151734 Hom.: 18186 Cov.: 31 AF XY: 0.476 AC XY: 35309 AN XY: 74112

Gnomad4 AFR AF: 0.580

Gnomad4 AMR AF: 0.482

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.343

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.497

Alfa AF: 0.467 Hom.: 5195

Bravo AF: 0.494

Asia WGS AF: 0.394 AC: 1373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.43

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: rs10844258; hg19: chr12-32768836;