12-32564054-T-G

Variant names:

• chr12-32564054-T-G
• rs61926167
• NM_001370298.3:c.167-83T>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001370298.3(FGD4):​c.167-83T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,068,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00019 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGD4 NM_001370298.3 intron
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD4	NM_001370298.3	c.167-83T>G		intron_variant	Intron 1 of 16	ENST00000534526.7	NP_001357227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD4	ENST00000534526.7	c.167-83T>G		intron_variant	Intron 1 of 16	5	NM_001370298.3	ENSP00000449273.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 25 AN: 132774 Hom.: 0 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.000152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000174

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 112 AN: 1068758 Hom.: 0 AF XY: 0.000121 AC XY: 63 AN XY: 522778

Gnomad4 AFR exome AF: 0.0000454

Gnomad4 AMR exome AF: 0.000216

Gnomad4 ASJ exome AF: 0.0000570

Gnomad4 EAS exome AF: 0.000242

Gnomad4 SAS exome AF: 0.000516

Gnomad4 FIN exome AF: 0.000108

Gnomad4 NFE exome AF: 0.0000741

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000188 AC: 25 AN: 132848 Hom.: 0 Cov.: 25 AF XY: 0.000218 AC XY: 14 AN XY: 64176

Gnomad4 AFR AF: 0.000151

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000221

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000231

Gnomad4 NFE AF: 0.000174

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.17

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; COSMIC: COSV56789722;