9-127809806-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.1183G>A(p.Ala395Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 151,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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=0.09766406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FPGS	NM_004957.6	c.1183G>A	p.Ala395Thr	missense_variant	12/15	ENST00000373247.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FPGS	ENST00000373247.7	c.1183G>A	p.Ala395Thr	missense_variant	12/15	1	NM_004957.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151152 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

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

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151152 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73830

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Sep 09, 2021

The c.1183G>A (p.A395T) alteration is located in exon 12 (coding exon 12) of the FPGS gene. This alteration results from a G to A substitution at nucleotide position 1183, causing the alanine (A) at amino acid position 395 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	0.076
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.037	B;B;.
Vest4		0.18
MutPred		0.36		.;Gain of phosphorylation at A395 (P = 0.0427);.;
MVP		0.26
MPC		0.61
ClinPred		0.26	T
GERP RS		3.3
Varity_R		0.030
gMVP		0.29

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: rs982514535; hg19: chr9-130572085;