Variant 9-127803012-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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 (★).

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

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 made for transcript

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=0.2512138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 15	ENST00000373247.7	NP_004948.4	Q05932-1
FPGS	NM_001288803.1 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 14		NP_001275732.1	Q05932-4
FPGS	XM_005251864.5 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 16		XP_005251921.1
FPGS	NR_110170.1 link	n.155C>T		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 15	1	NM_004957.6	ENSP00000362344.2		Q05932-1

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

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1313156

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

646940

show subpopulations

Gnomad4 AFR exome

AF:

0.00100

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:

9.53e-7

Gnomad4 OTH exome

AF:

0.0000368

GnomAD4 genome

AF:

0.000263

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000941

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000283

ExAC

AF:

0.0000644

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88C>T (p.R30W) alteration is located in exon 1 (coding exon 1) of the FPGS gene. This alteration results from a C to T substitution at nucleotide position 88, causing the arginine (R) at amino acid position 30 to be replaced by a tryptophan (W). 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

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

.;T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.91

D;D;D;.

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

M;.;M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.2

N;.;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0040

D;.;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

0.45

P;.;P;.

Vest4

0.39

MutPred

0.47

Loss of disorder (P = 0.0236);Loss of disorder (P = 0.0236);Loss of disorder (P = 0.0236);Loss of disorder (P = 0.0236);

MVP

0.44

MPC

1.6

ClinPred

0.88

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.21

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over