Variant 9-127813236-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004957.6(FPGS):c.1396C>T(p.Arg466Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00993 in 1,607,698 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0084 ( 13 hom., cov: 32)

Exomes 𝑓: 0.010 ( 104 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.67

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010068268).

BP6

Variant 9-127813236-C-T is Benign according to our data. Variant chr9-127813236-C-T is described in ClinVar as [Benign]. Clinvar id is 3341528.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6 link	c.1396C>T	p.Arg466Cys	missense_variant	Exon 15 of 15	ENST00000373247.7	NP_004948.4	Q05932-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7 link	c.1396C>T	p.Arg466Cys	missense_variant	Exon 15 of 15	1	NM_004957.6	ENSP00000362344.2		Q05932-1

Frequencies

GnomAD3 genomes

AF:

0.00837

AC:

1273

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00952

AC:

2329

AN:

244654

Hom.:

AF XY:

0.00950

AC XY:

1259

AN XY:

132512

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.00375

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00349

Gnomad FIN exome

AF:

0.0322

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.00969

GnomAD4 exome

AF:

0.0101

AC:

14692

AN:

1455404

Hom.:

104

Cov.:

AF XY:

0.00987

AC XY:

7139

AN XY:

723478

show subpopulations

Gnomad4 AFR exome

AF:

0.00168

Gnomad4 AMR exome

AF:

0.00274

Gnomad4 ASJ exome

AF:

0.00331

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00335

Gnomad4 FIN exome

AF:

0.0308

Gnomad4 NFE exome

AF:

0.0109

Gnomad4 OTH exome

AF:

0.00785

GnomAD4 genome

AF:

0.00836

AC:

1273

AN:

152294

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

697

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00144

Gnomad4 AMR

AF:

0.00542

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.0313

Gnomad4 NFE

AF:

0.0109

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.0100

Hom.:

Bravo

AF:

0.00672

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00977

AC:

1186

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

FPGS: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

.;D;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

3.4

.;M;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.8

D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0090

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.69

MVP

0.61

MPC

1.1

ClinPred

0.026

GERP RS

5.0

Varity_R

0.39

gMVP

0.73

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