9-127804639-T-A

Position:

• chr9-127804639-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004957.6(FPGS):​c.325T>A​(p.Ser109Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FPGS	NM_004957.6	c.325T>A	p.Ser109Thr	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.325T>A	p.Ser109Thr	missense_variant	4/15	1	NM_004957.6	ENSP00000362344.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.325T>A (p.S109T) alteration is located in exon 4 (coding exon 4) of the FPGS gene. This alteration results from a T to A substitution at nucleotide position 325, causing the serine (S) at amino acid position 109 to be replaced by a threonine (T). 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	0.32
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;T;T;.;T;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Uncertain	2.6	M;.;M;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D;.;D;N;D;N;N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;.;D;T;D;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;D
Polyphen		1.0	D;.;D;.;.;.;.
Vest4		0.92
MutPred		0.84		Loss of glycosylation at S109 (P = 0.0573);Loss of glycosylation at S109 (P = 0.0573);Loss of glycosylation at S109 (P = 0.0573);Loss of glycosylation at S109 (P = 0.0573);.;.;.;
MVP		0.81
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.94

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

Other links and lift over

dbSNP: rs1829737474; hg19: chr9-130566918;