9-127802952-G-T

Variant summary

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

The NM_004957.6(FPGS):​c.28G>T​(p.Ala10Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 29)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FPGS
NM_004957.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.806
Variant links:
Genes affected
FPGS (HGNC:3824): (folylpolyglutamate synthase) This gene encodes the folylpolyglutamate synthetase enzyme. This enzyme has a central role in establishing and maintaining both cytosolic and mitochondrial folylpolyglutamate concentrations and, therefore, is essential for folate homeostasis and the survival of proliferating cells. This enzyme catalyzes the ATP-dependent addition of glutamate moieties to folate and folate derivatives. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Jan 2014]

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=0.05773008).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FPGSNM_004957.6 linkuse as main transcriptc.28G>T p.Ala10Ser missense_variant 1/15 ENST00000373247.7 NP_004948.4 Q05932-1
FPGSNM_001288803.1 linkuse as main transcriptc.28G>T p.Ala10Ser missense_variant 1/14 NP_001275732.1 Q05932-4
FPGSXM_005251864.5 linkuse as main transcriptc.28G>T p.Ala10Ser missense_variant 1/16 XP_005251921.1
FPGSNR_110170.1 linkuse as main transcriptn.95G>T non_coding_transcript_exon_variant 1/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FPGSENST00000373247.7 linkuse as main transcriptc.28G>T p.Ala10Ser missense_variant 1/151 NM_004957.6 ENSP00000362344.2 Q05932-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1259278
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
616202
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
29

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 submitterclinical testingAmbry GeneticsSep 11, 2024The c.28G>T (p.A10S) alteration is located in exon 1 (coding exon 1) of the FPGS gene. This alteration results from a G to T substitution at nucleotide position 28, causing the alanine (A) at amino acid position 10 to be replaced by a serine (S). 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
0.095
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
12
DANN
Benign
0.67
DEOGEN2
Benign
0.011
.;T;T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.61
T;T;T;.
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.058
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N;.;N;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
0.010
N;.;N;N
REVEL
Benign
0.022
Sift
Benign
0.67
T;.;T;T
Sift4G
Benign
0.65
T;T;T;T
Polyphen
0.0050
B;.;B;.
Vest4
0.15
MutPred
0.37
Gain of phosphorylation at A10 (P = 0.0323);Gain of phosphorylation at A10 (P = 0.0323);Gain of phosphorylation at A10 (P = 0.0323);Gain of phosphorylation at A10 (P = 0.0323);
MVP
0.18
MPC
0.56
ClinPred
0.055
T
GERP RS
1.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.052
gMVP
0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130565231; API