Genetic Variant FPGS:p.Arg5Gly (chr9-127802937-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004957.6(FPGS):c.13C>G(p.Arg5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000805 in 1,242,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R5W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.360

Publications

0 publications found

Variant links:

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]

FPGS links:

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ACMG classification

Classification was made for transcript

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=0.084561825).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FPGS	NM_004957.6	MANE Select	c.13C>G	p.Arg5Gly	missense	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.13C>G	p.Arg5Gly	missense	Exon 1 of 14	NP_001275732.1	Q05932-4
FPGS	NR_110170.1		n.80C>G		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FPGS	ENST00000373247.7	TSL:1 MANE Select	c.13C>G	p.Arg5Gly	missense	Exon 1 of 15	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.20C>G		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000910448.1		c.13C>G	p.Arg5Gly	missense	Exon 1 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.05e-7

AC:

AN:

1242020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

606248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24384

American (AMR)

AF:

0.00

AC:

AN:

13948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19034

East Asian (EAS)

AF:

0.00

AC:

AN:

27276

South Asian (SAS)

AF:

0.00

AC:

AN:

59956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3576

European-Non Finnish (NFE)

AF:

9.88e-7

AC:

AN:

1012444

Other (OTH)

AF:

0.00

AC:

AN:

51032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.022

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.36

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.2

REVEL

Benign

0.034

Sift

Uncertain

0.026

Sift4G

Uncertain

0.051

Polyphen

0.010

Vest4

0.24

MutPred

0.30

Loss of helix (P = 0.0093)

MVP

0.23

MPC

0.77

ClinPred

0.097

GERP RS

2.8

PromoterAI

-0.043

Neutral

(source)

Varity_R

0.058

gMVP

0.46

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over