12-95172742-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018351.4(FGD6):c.2444C>T(p.Ser815Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,438,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FGD6 NM_018351.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1501039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD6	NM_018351.4	c.2444C>T	p.Ser815Leu	missense_variant, splice_region_variant	3/21	ENST00000343958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD6	ENST00000343958.9	c.2444C>T	p.Ser815Leu	missense_variant, splice_region_variant	3/21	1	NM_018351.4	P1
FGD6	ENST00000549499.1	c.2444C>T	p.Ser815Leu	missense_variant, splice_region_variant	3/16	1
FGD6	ENST00000451107.3	c.19C>T	p.Gln7Ter	stop_gained, splice_region_variant, NMD_transcript_variant	2/20	1
FGD6	ENST00000546711.5	c.2444C>T	p.Ser815Leu	missense_variant, splice_region_variant	3/19	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243208 Hom.: 0 AF XY: 0.00000762 AC XY: 1 AN XY: 131298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1438288 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 712808

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: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

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

May 04, 2022

The c.2444C>T (p.S815L) alteration is located in exon 3 (coding exon 3) of the FGD6 gene. This alteration results from a C to T substitution at nucleotide position 2444, causing the serine (S) at amino acid position 815 to be replaced by a leucine (L). 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	0.074
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.018	T;.;T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	0.67	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.0010	B;.;.
Vest4		0.11
MutPred		0.27		Loss of glycosylation at S815 (P = 0.0085);Loss of glycosylation at S815 (P = 0.0085);Loss of glycosylation at S815 (P = 0.0085);
MVP		0.65
MPC		0.14
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.13
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs774885571; hg19: chr12-95566518; COSMIC: COSV59696376;