Variant chr3-14819596-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152536.4(FGD5):c.525G>T(p.Glu175Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000087 in 1,551,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

FGD5
NM_152536.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.11

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010289907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGD5	NM_152536.4 linkuse as main transcript	c.525G>T	p.Glu175Asp	missense_variant	1/20	ENST00000285046.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGD5	ENST00000285046.10 linkuse as main transcript	c.525G>T	p.Glu175Asp	missense_variant	1/20	1	NM_152536.4	P1	Q6ZNL6-1
FGD5	ENST00000543601.5 linkuse as main transcript	c.-199G>T		5_prime_UTR_variant	1/19	1
FGD5	ENST00000640506.1 linkuse as main transcript	c.654G>T	p.Glu218Asp	missense_variant	2/2	5

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000111

AC:

AN:

153510

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

81462

show subpopulations

Gnomad AFR exome

AF:

0.00139

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000393

AC:

AN:

1399238

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

690138

show subpopulations

Gnomad4 AFR exome

AF:

0.000981

Gnomad4 AMR exome

AF:

0.000308

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.000525

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000427

Hom.:

Bravo

AF:

0.000782

ExAC

AF:

0.0000863

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2024

The c.525G>T (p.E175D) alteration is located in exon 1 (coding exon 1) of the FGD5 gene. This alteration results from a G to T substitution at nucleotide position 525, causing the glutamic acid (E) at amino acid position 175 to be replaced by an aspartic acid (D). 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

0.088

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.10

DANN

Benign

0.96

DEOGEN2

Benign

0.0034

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.28

.;N

REVEL

Benign

0.080

Sift

Benign

0.11

.;T

Sift4G

Benign

0.38

.;T

Polyphen

0.18

.;B

Vest4

0.059

MVP

0.48

MPC

0.14

ClinPred

0.014

GERP RS

-7.4

Varity_R

0.081

gMVP

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over