dbSNP rs34330923: FPGS:p.Leu81Leu (chr9-127804389-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_004957.6(FPGS):c.243G>A(p.Leu81Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,614,214 control chromosomes in the GnomAD database, including 200 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 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.013 ( 184 hom. )

Consequence

FPGS
NM_004957.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.187

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP7

Synonymous conserved (PhyloP=0.187 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6 link	c.243G>A	p.Leu81Leu	synonymous_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.243G>A	p.Leu81Leu	synonymous_variant	Exon 2 of 15	1	NM_004957.6	ENSP00000362344.2		Q05932-1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1747

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00889

Gnomad FIN

AF:

0.0396

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0130

AC:

3274

AN:

251298

AF XY:

0.0129

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0396

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0135

AC:

19668

AN:

1461860

Hom.:

184

Cov.:

AF XY:

0.0133

AC XY:

9638

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

33480

American (AMR)

AF:

0.00505

AC:

226

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00620

AC:

535

AN:

86258

European-Finnish (FIN)

AF:

0.0382

AC:

2042

AN:

53404

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0144

AC:

16041

AN:

1112000

Other (OTH)

AF:

0.0102

AC:

619

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1140

2280

3420

4560

5700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0115

AC:

1745

AN:

152354

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

940

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41582

American (AMR)

AF:

0.00856

AC:

131

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00869

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0396

AC:

421

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0150

AC:

1021

AN:

68026

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00926

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0122

EpiControl

AF:

0.0113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

5.9

(source)

DANN

Benign

0.83

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs34330923

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