rs34354111

Positions:

• chr9-127813423-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004957.6(FPGS):​c.1583G>C​(p.Ser528Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68

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]

FPGS (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07999253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FPGS	NM_004957.6	c.1583G>C	p.Ser528Thr	missense_variant	15/15	ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7	c.1583G>C	p.Ser528Thr	missense_variant	15/15	1	NM_004957.6	ENSP00000362344.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.20	.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	.;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.79	N;N;N
REVEL	Benign	0.018
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.095
MutPred		0.20		.;Loss of helix (P = 0.0237);.;
MVP		0.16
MPC		0.56
ClinPred		0.23	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.21

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: rs34354111; hg19: chr9-130575702;