9-127809726-G-T

Variant names:

• chr9-127809726-G-T
• rs1186491225
• NM_004957.6:c.1103G>T

Variant summary

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

The NM_004957.6(FPGS):​c.1103G>T​(p.Arg368Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 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: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.384

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=0.08199692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6	c.1103G>T	p.Arg368Leu	missense_variant	Exon 12 of 15	ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7	c.1103G>T	p.Arg368Leu	missense_variant	Exon 12 of 15	1	NM_004957.6	ENSP00000362344.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000478 AC: 1 AN: 209244 Hom.: 0 AF XY: 0.00000852 AC XY: 1 AN XY: 117348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000190

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436164 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0076	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.32	T;.
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	0.020	.;N
REVEL	Benign	0.025
Sift	Benign	0.042	.;D
Sift4G	Uncertain	0.029	D;D
Vest4		0.21
MutPred		0.28		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.13
ClinPred		0.61	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1186491225; hg19: chr9-130572005;