9-127803013-G-A

Variant summary

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

The NM_004957.6(FPGS):c.89G>A(p.Arg30Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000614 in 1,465,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

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=0.19289461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FPGS	NM_004957.6	c.89G>A	p.Arg30Gln	missense_variant	1/15	ENST00000373247.7
FPGS	NM_001288803.1	c.89G>A	p.Arg30Gln	missense_variant	1/14
FPGS	XM_005251864.5	c.89G>A	p.Arg30Gln	missense_variant	1/16
FPGS	NR_110170.1	n.156G>A		non_coding_transcript_exon_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FPGS	ENST00000373247.7	c.89G>A	p.Arg30Gln	missense_variant	1/15	1	NM_004957.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000581 AC: 4 AN: 68814 Hom.: 0 AF XY: 0.0000751 AC XY: 3 AN XY: 39936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 6 AN: 1313362 Hom.: 0 Cov.: 35 AF XY: 0.00000773 AC XY: 5 AN XY: 647080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000249

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 AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

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

Aug 17, 2021

The c.89G>A (p.R30Q) alteration is located in exon 1 (coding exon 1) of the FPGS gene. This alteration results from a G to A substitution at nucleotide position 89, causing the arginine (R) at amino acid position 30 to be replaced by a glutamine (Q). 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	0.099
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.090
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D;D;.
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N;.;N;N
REVEL	Benign	0.12
Sift	Benign	0.044	D;.;D;D
Sift4G	Uncertain	0.043	D;D;T;D
Polyphen		0.95	P;.;D;.
Vest4		0.26
MutPred		0.46		Loss of MoRF binding (P = 0.0466);Loss of MoRF binding (P = 0.0466);Loss of MoRF binding (P = 0.0466);Loss of MoRF binding (P = 0.0466);
MVP		0.35
MPC		1.0
ClinPred		0.26	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.16
gMVP		0.25

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: rs1450638962; hg19: chr9-130565292;