dbSNP rs41307463: FPGS:c.822+48C>T (chr9-127808359-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_004957.6(FPGS):c.822+48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,558,978 control chromosomes in the GnomAD database, including 444 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 0.016 ( 36 hom., cov: 32)

Exomes 𝑓: 0.022 ( 408 hom. )

Consequence

FPGS
NM_004957.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.540

Publications

3 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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new If you want to explore the variant's impact on the transcript NM_004957.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2504/152192) while in subpopulation NFE AF = 0.0251 (1707/68014). AF 95% confidence interval is 0.0241. There are 36 homozygotes in GnomAd4. There are 1129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

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	Effect	Exon Rank	Protein	UniProt
FPGS	NM_004957.6	MANE Select	c.822+48C>T	intron	N/A	NP_004948.4
FPGS	NM_001288803.1		c.744+48C>T	intron	N/A	NP_001275732.1	Q05932-4
FPGS	NM_001018078.2		c.672+48C>T	intron	N/A	NP_001018088.1	Q05932-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FPGS	ENST00000373247.7	TSL:1 MANE Select	c.822+48C>T	intron	N/A	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.810+48C>T	intron	N/A
FPGS	ENST00000910448.1		c.924+48C>T	intron	N/A	ENSP00000580507.1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2506

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0251

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0181

AC:

4528

AN:

249952

AF XY:

0.0183

show subpopulations

Gnomad AFR exome

AF:

0.00390

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0341

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00695

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0220

AC:

31018

AN:

1406786

Hom.:

408

Cov.:

AF XY:

0.0220

AC XY:

15445

AN XY:

702944

show subpopulations

African (AFR)

AF:

0.00424

AC:

137

AN:

32304

American (AMR)

AF:

0.0140

AC:

623

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0318

AC:

819

AN:

25740

East Asian (EAS)

AF:

0.0000762

AC:

AN:

39370

South Asian (SAS)

AF:

0.0142

AC:

1207

AN:

85096

European-Finnish (FIN)

AF:

0.00719

AC:

383

AN:

53292

Middle Eastern (MID)

AF:

0.0216

AC:

123

AN:

5682

European-Non Finnish (NFE)

AF:

0.0250

AC:

26515

AN:

1062178

Other (OTH)

AF:

0.0206

AC:

1208

AN:

58504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1558

3116

4674

6232

7790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

980

1960

2940

3920

4900

<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:

0.0165

AC:

2504

AN:

152192

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1129

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00448

AC:

186

AN:

41522

American (AMR)

AF:

0.0215

AC:

328

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.0137

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00471

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0251

AC:

1707

AN:

68014

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

129

258

388

517

646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0215

Hom.:

Bravo

AF:

0.0169

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.3

(source)

DANN

Benign

0.80

PhyloP100

-0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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