Variant 9-127809781-G-C 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.1158G>C(p.Gln386His) variant causes a missense change. The variant allele was found at a frequency of 0.0000884 in 1,560,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.76

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 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=0.09750578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FPGS	NM_004957.6 linkuse as main transcript	c.1158G>C	p.Gln386His	missense_variant	12/15	ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7 linkuse as main transcript	c.1158G>C	p.Gln386His	missense_variant	12/15	1	NM_004957.6	ENSP00000362344	P1	Q05932-1

Frequencies

GnomAD3 genomes

AF:

0.000462

AC:

AN:

151566

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000624

AC:

AN:

176412

Hom.:

AF XY:

0.0000599

AC XY:

AN XY:

100122

show subpopulations

Gnomad AFR exome

AF:

0.00125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000385

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000483

AC:

AN:

1408598

Hom.:

Cov.:

AF XY:

0.0000486

AC XY:

AN XY:

699938

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.0000258

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000456

Gnomad4 OTH exome

AF:

0.000172

GnomAD4 genome

AF:

0.000461

AC:

AN:

151680

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74148

show subpopulations

Gnomad4 AFR

AF:

0.00162

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000472

ExAC

AF:

0.0000545

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2023

The c.1158G>C (p.Q386H) alteration is located in exon 12 (coding exon 12) of the FPGS gene. This alteration results from a G to C substitution at nucleotide position 1158, causing the glutamine (Q) at amino acid position 386 to be replaced by a histidine (H). 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

0.21

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.27

.;T;.

Eigen

Benign

-0.039

Eigen_PC

Benign

-0.085

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.098

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;.

MutationTaster

Benign

1.0

D;D;D;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.030

B;B;.

Vest4

0.56

MutPred

0.39

.;Loss of MoRF binding (P = 0.0932);.;

MVP

0.41

MPC

0.64

ClinPred

0.049

GERP RS

2.3

Varity_R

0.17

gMVP

0.59

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