9-127813332-G-C

Variant names:

• chr9-127813332-G-C
• rs750428981
• NM_004957.6:c.1492G>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.1492G>C​(p.Ala498Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069039196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6	c.1492G>C	p.Ala498Pro	missense_variant	Exon 15 of 15	ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7	c.1492G>C	p.Ala498Pro	missense_variant	Exon 15 of 15	1	NM_004957.6	ENSP00000362344.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460510 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.028
DANN	Benign	0.73
DEOGEN2	Benign	0.20	.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.064
MutPred		0.34		.;Gain of sheet (P = 0.0061);.;
MVP		0.43
MPC		0.79
ClinPred		0.063	T
GERP RS		-3.9
Varity_R		0.069
gMVP		0.45

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: rs750428981; hg19: chr9-130575611;