9-127804688-C-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_004957.6(FPGS):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
FPGS
NM_004957.6 missense
NM_004957.6 missense
Scores
13
3
3
Clinical Significance
Conservation
PhyloP100: 7.28
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.754
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FPGS | NM_004957.6 | c.374C>T | p.Thr125Met | missense_variant | 4/15 | ENST00000373247.7 | NP_004948.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FPGS | ENST00000373247.7 | c.374C>T | p.Thr125Met | missense_variant | 4/15 | 1 | NM_004957.6 | ENSP00000362344 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251478Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727216
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GnomAD4 genome Cov.: 32
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32
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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 | Jun 05, 2024 | The c.374C>T (p.T125M) alteration is located in exon 4 (coding exon 4) of the FPGS gene. This alteration results from a C to T substitution at nucleotide position 374, causing the threonine (T) at amino acid position 125 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;T;D;T;.;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;.;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;.;H;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;.;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;.;D;.;.;.;.
Vest4
MVP
MPC
1.6
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at