dbSNP rs181035766: FPGS:p.Arg332Ser (chr9-127808825-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004957.6(FPGS):c.996G>C(p.Arg332Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,563,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0950

Publications

0 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017648786).

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.996G>C	p.Arg332Ser	missense	Exon 11 of 15	NP_004948.4
FPGS	NM_001288803.1		c.918G>C	p.Arg306Ser	missense	Exon 10 of 14	NP_001275732.1	Q05932-4
FPGS	NM_001018078.2		c.846G>C	p.Arg282Ser	missense	Exon 11 of 15	NP_001018088.1	Q05932-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FPGS	ENST00000373247.7	TSL:1 MANE Select	c.996G>C	p.Arg332Ser	missense	Exon 11 of 15	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.984G>C		non_coding_transcript_exon	Exon 11 of 15
FPGS	ENST00000910448.1		c.1098G>C	p.Arg366Ser	missense	Exon 12 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000227

AC:

AN:

171588

AF XY:

0.000251

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000342

Gnomad ASJ exome

AF:

0.000116

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000344

Gnomad OTH exome

AF:

0.000217

GnomAD4 exome

AF:

0.000262

AC:

369

AN:

1410844

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

181

AN XY:

697324

show subpopulations

African (AFR)

AF:

0.0000312

AC:

AN:

32066

American (AMR)

AF:

0.000269

AC:

AN:

37238

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25252

East Asian (EAS)

AF:

0.00

AC:

AN:

36562

South Asian (SAS)

AF:

0.000125

AC:

AN:

80094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.000310

AC:

337

AN:

1085956

Other (OTH)

AF:

0.000171

AC:

AN:

58462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000243

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.000588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000273

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.000153

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

0.097

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.1

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.0073

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.36

M_CAP

Benign

0.0053

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.96

PhyloP100

-0.095

PROVEAN

Benign

0.090

REVEL

Benign

0.0080

Sift

Benign

0.094

Sift4G

Benign

0.074

Vest4

0.18

MVP

0.16

ClinPred

0.012

GERP RS

0.12

Varity_R

0.082

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over