Genetic Variant FPGS:p.Arg30Trp (chr9-127803012-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004957.6(FPGS):c.88C>T(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,465,212 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R30Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000022 ( 1 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.925

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2512138).

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.88C>T	p.Arg30Trp	missense	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.88C>T	p.Arg30Trp	missense	Exon 1 of 14	NP_001275732.1	Q05932-4
FPGS	NR_110170.1		n.155C>T		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.88C>T	p.Arg30Trp	missense	Exon 1 of 15	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.95C>T		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000910448.1		c.88C>T	p.Arg30Trp	missense	Exon 1 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000943

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD2 exomes

AF:

0.0000145

AC:

AN:

68762

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000788

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:

0.00

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1313156

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

646940

show subpopulations

African (AFR)

AF:

0.00100

AC:

AN:

25976

American (AMR)

AF:

0.00

AC:

AN:

24088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22560

East Asian (EAS)

AF:

0.00

AC:

AN:

28570

South Asian (SAS)

AF:

0.00

AC:

AN:

70774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3886

European-Non Finnish (NFE)

AF:

9.53e-7

AC:

AN:

1048894

Other (OTH)

AF:

0.0000368

AC:

AN:

54348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000263

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000941

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000283

ExAC

AF:

0.0000644

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

PhyloP100

0.93

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.2

REVEL

Benign

0.16

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0030

Polyphen

0.45

Vest4

0.39

MutPred

0.47

Loss of disorder (P = 0.0236)

MVP

0.44

MPC

1.6

ClinPred

0.88

GERP RS

5.2

PromoterAI

0.047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.21

gMVP

0.34

Mutation Taster

=62/38

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over