NM_004957.6:c.1103G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/18 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R368Q) has been classified as Uncertain significance.

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08199692).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004957.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	NM_004957.6	MANE Select	c.1103G>T	p.Arg368Leu	missense	Exon 12 of 15	NP_004948.4
	FPGS	NM_001288803.1		c.1025G>T	p.Arg342Leu	missense	Exon 11 of 14	NP_001275732.1	Q05932-4
	FPGS	NM_001018078.2		c.953G>T	p.Arg318Leu	missense	Exon 12 of 15	NP_001018088.1	Q05932-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	ENST00000373247.7	TSL:1 MANE Select	c.1103G>T	p.Arg368Leu	missense	Exon 12 of 15	ENSP00000362344.2	Q05932-1
	FPGS	ENST00000460181.5	TSL:1	n.1091G>T		non_coding_transcript_exon	Exon 12 of 15
	FPGS	ENST00000910448.1		c.1205G>T	p.Arg402Leu	missense	Exon 13 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000478 AC: 1 AN: 209244 AF XY: 0.00000852

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31982

American (AMR) AF: 0.00 AC: 0 AN: 43588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 38310

South Asian (SAS) AF: 0.00 AC: 0 AN: 85332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107590

Other (OTH) AF: 0.00 AC: 0 AN: 59664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.99	T
PhyloP100		0.38
PROVEAN	Benign	0.020	N
REVEL	Benign	0.025
Sift	Benign	0.042	D
Sift4G	Uncertain	0.029	D
Vest4		0.21
MutPred		0.28		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
Varity_R		0.13
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1186491225; hg19: chr9-130572005;