dbSNP rs41306702: FPGS:p.Arg85Trp (chr9-127804399-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004957.6(FPGS):c.253C>T(p.Arg85Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,170 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 20 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.30

Publications

18 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018259734).

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6 link	c.253C>T	p.Arg85Trp	missense_variant	Exon 2 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.253C>T	p.Arg85Trp	missense_variant	Exon 2 of 15	1	NM_004957.6	ENSP00000362344.2		Q05932-1

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00397

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00261

AC:

655

AN:

251244

AF XY:

0.00250

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00388

AC:

5670

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2701

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00224

AC:

100

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00141

AC:

122

AN:

86258

European-Finnish (FIN)

AF:

0.00243

AC:

130

AN:

53404

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00456

AC:

5069

AN:

1111996

Other (OTH)

AF:

0.00381

AC:

230

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

315

630

945

1260

1575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.00241

AC:

367

AN:

152316

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

175

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41572

American (AMR)

AF:

0.00163

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00397

AC:

270

AN:

68020

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

101

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:

0.00361

Hom.:

Bravo

AF:

0.00248

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00243

AC:

295

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T;D;T;.;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D;D;.;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.018

T;T;T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

4.0

H;.;H;.;.;.;.

PhyloP100

1.3

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.3

D;.;D;D;D;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;.;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;.;.;.

Vest4

0.87

MVP

0.53

MPC

1.6

ClinPred

0.14

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.86

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over