12-95208900-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018351.4(FGD6):c.2384A>T(p.Glu795Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGD6 NM_018351.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

Genes affected

FGD6 (HGNC:21740): (FYVE, RhoGEF and PH domain containing 6) Predicted to enable guanyl-nucleotide exchange factor activity and small GTPase binding activity. Predicted to be involved in several processes, including filopodium assembly; regulation of GTPase activity; and regulation of cell shape. Predicted to be located in Golgi apparatus; lamellipodium; and ruffle. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3105476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD6	NM_018351.4	c.2384A>T	p.Glu795Val	missense_variant	2/21	ENST00000343958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD6	ENST00000343958.9	c.2384A>T	p.Glu795Val	missense_variant	2/21	1	NM_018351.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.2384A>T (p.E795V) alteration is located in exon 2 (coding exon 2) of the FGD6 gene. This alteration results from a A to T substitution at nucleotide position 2384, causing the glutamic acid (E) at amino acid position 795 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.069	T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.96	D;.;.
Vest4		0.45
MutPred		0.29		Loss of disorder (P = 0.0382);Loss of disorder (P = 0.0382);Loss of disorder (P = 0.0382);
MVP		0.50
MPC		0.52
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-95602676;