9-93002925-C-T

Variant names:

• chr9-93002925-C-T
• rs752532031
• NM_001083536.2:c.454C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001083536.2(FGD3):​c.454C>T​(p.His152Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 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)
• Consequence: FGD3 NM_001083536.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001327
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0970
• Publications: 0 publications found

Genes affected

FGD3 (HGNC:16027): (FYVE, RhoGEF and PH domain containing 3) 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03918177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGD3	NM_001083536.2	c.454C>T	p.His152Tyr	missense_variant, splice_region_variant	Exon 4 of 18	ENST00000375482.8	NP_001077005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGD3	ENST00000375482.8	c.454C>T	p.His152Tyr	missense_variant, splice_region_variant	Exon 4 of 18	1	NM_001083536.2	ENSP00000364631.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.454C>T (p.H152Y) alteration is located in exon 4 (coding exon 2) of the FGD3 gene. This alteration results from a C to T substitution at nucleotide position 454, causing the histidine (H) at amino acid position 152 to be replaced by a tyrosine (Y). 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	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.8
DANN	Benign	0.34
DEOGEN2	Benign	0.058	T;.;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.35	.;T;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L;L;L;L
PhyloP100		-0.097
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.080	N;N;.;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.13	B;.;B;B
Vest4		0.19
MutPred		0.25		Loss of disorder (P = 0.05);Loss of disorder (P = 0.05);Loss of disorder (P = 0.05);Loss of disorder (P = 0.05);
MVP		0.51
MPC		0.095
ClinPred		0.12	T
GERP RS		-1.4
Varity_R		0.014
gMVP		0.097
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752532031; hg19: chr9-95765207;