chr3-14924095-C-T

Variant summary

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

The NM_152536.4(FGD5):​c.4025C>T​(p.Ser1342Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S1342W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

FGD5
NM_152536.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.96
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-AS1 (HGNC:40410): (FGD5 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGD5NM_152536.4 linkc.4025C>T p.Ser1342Leu missense_variant Exon 17 of 20 ENST00000285046.10 NP_689749.3 Q6ZNL6-1A0A2X0SFF2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGD5ENST00000285046.10 linkc.4025C>T p.Ser1342Leu missense_variant Exon 17 of 20 1 NM_152536.4 ENSP00000285046.5 Q6ZNL6-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249214
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135196
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461700
Hom.:
0
Cov.:
34
AF XY:
0.0000151
AC XY:
11
AN XY:
727132
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.0000414
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4025C>T (p.S1342L) alteration is located in exon 17 (coding exon 17) of the FGD5 gene. This alteration results from a C to T substitution at nucleotide position 4025, causing the serine (S) at amino acid position 1342 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
0.096
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.41
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.037
T;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.041
D
MetaRNN
Uncertain
0.55
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.8
D;D
REVEL
Benign
0.14
Sift
Uncertain
0.010
D;D
Sift4G
Uncertain
0.024
D;D
Polyphen
0.97
D;P
Vest4
0.61
MVP
0.42
MPC
0.55
ClinPred
0.76
D
GERP RS
4.9
Varity_R
0.34
gMVP
0.40

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.

Other links and lift over

dbSNP: rs369533231; hg19: chr3-14965602; API