NM_152536.4:c.4051C>A

Variant names:

• chr3-14924121-C-A
• rs761749889
• NM_152536.4:c.4051C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152536.4(FGD5):​c.4051C>A​(p.Pro1351Thr) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1351L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGD5 NM_152536.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 0 publications found

Genes affected

FGD5 (HGNC:19117): (FYVE, RhoGEF and PH domain containing 5) 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. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

FGD5-AS1 (HGNC:40410): (FGD5 antisense RNA 1)

LOC105376963 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3943385).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152536.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD5	NM_152536.4	MANE Select	c.4051C>A	p.Pro1351Thr	missense	Exon 17 of 20	NP_689749.3
	FGD5	NM_001320276.2		c.4051C>A	p.Pro1351Thr	missense	Exon 17 of 19	NP_001307205.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGD5	ENST00000285046.10	TSL:1 MANE Select	c.4051C>A	p.Pro1351Thr	missense	Exon 17 of 20	ENSP00000285046.5	Q6ZNL6-1
	FGD5	ENST00000543601.5	TSL:1	c.3328C>A	p.Pro1110Thr	missense	Exon 17 of 19	ENSP00000445949.1	B7ZM68
	FGD5	ENST00000476851.1	TSL:1	n.1588C>A		non_coding_transcript_exon	Exon 14 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.010
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.13
Sift	Benign	0.046	D
Sift4G	Benign	0.30	T
Polyphen		0.40	B
Vest4		0.60
MutPred		0.22		Gain of phosphorylation at P1351 (P = 0.0385)
MVP		0.35
MPC		0.68
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.47
gMVP		0.39
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs761749889; hg19: chr3-14965628; COSMIC: COSV99549653;