9-127802988-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004957.6(FPGS):c.64A>G(p.Ile22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,461,332 control chromosomes in the GnomAD database, including 331,092 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41171 hom., cov: 31)

Exomes 𝑓: 0.66 ( 289921 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0510

Publications

40 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.226459E-7).

BP6

Variant 9-127802988-A-G is Benign according to our data. Variant chr9-127802988-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

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
FPGS	NM_004957.6	MANE Select	c.64A>G	p.Ile22Val	missense	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.64A>G	p.Ile22Val	missense	Exon 1 of 14	NP_001275732.1
FPGS	NR_110170.1		n.131A>G		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FPGS	ENST00000373247.7	TSL:1 MANE Select	c.64A>G	p.Ile22Val	missense	Exon 1 of 15	ENSP00000362344.2
FPGS	ENST00000460181.5	TSL:1	n.71A>G		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000393706.6	TSL:2	c.64A>G	p.Ile22Val	missense	Exon 1 of 14	ENSP00000377309.2

Frequencies

GnomAD3 genomes

AF:

0.728

AC:

110439

AN:

151712

Hom.:

41131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.857

Gnomad AMI

AF:

0.637

Gnomad AMR

AF:

0.628

Gnomad ASJ

AF:

0.590

Gnomad EAS

AF:

0.965

Gnomad SAS

AF:

0.690

Gnomad FIN

AF:

0.783

Gnomad MID

AF:

0.583

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.683

GnomAD2 exomes

AF:

0.638

AC:

42882

AN:

67242

AF XY:

0.639

show subpopulations

Gnomad AFR exome

AF:

0.839

Gnomad AMR exome

AF:

0.582

Gnomad ASJ exome

AF:

0.556

Gnomad EAS exome

AF:

0.956

Gnomad FIN exome

AF:

0.777

Gnomad NFE exome

AF:

0.620

Gnomad OTH exome

AF:

0.597

GnomAD4 exome

AF:

0.662

AC:

866421

AN:

1309512

Hom.:

289921

Cov.:

AF XY:

0.662

AC XY:

426723

AN XY:

645006

show subpopulations

African (AFR)

AF:

0.861

AC:

22325

AN:

25942

American (AMR)

AF:

0.601

AC:

14132

AN:

23510

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

12858

AN:

22360

East Asian (EAS)

AF:

0.970

AC:

27751

AN:

28598

South Asian (SAS)

AF:

0.671

AC:

47089

AN:

70138

European-Finnish (FIN)

AF:

0.773

AC:

25675

AN:

33232

Middle Eastern (MID)

AF:

0.548

AC:

2117

AN:

3864

European-Non Finnish (NFE)

AF:

0.648

AC:

678616

AN:

1047698

Other (OTH)

AF:

0.662

AC:

35858

AN:

54170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

15687

31374

47061

62748

78435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18344

36688

55032

73376

91720

<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:

0.728

AC:

110528

AN:

151820

Hom.:

41171

Cov.:

AF XY:

0.731

AC XY:

54217

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.858

AC:

35577

AN:

41476

American (AMR)

AF:

0.627

AC:

9583

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.590

AC:

2045

AN:

3468

East Asian (EAS)

AF:

0.966

AC:

4939

AN:

5114

South Asian (SAS)

AF:

0.690

AC:

3315

AN:

4806

European-Finnish (FIN)

AF:

0.783

AC:

8274

AN:

10562

Middle Eastern (MID)

AF:

0.582

AC:

170

AN:

292

European-Non Finnish (NFE)

AF:

0.658

AC:

44612

AN:

67814

Other (OTH)

AF:

0.680

AC:

1438

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1454

2908

4362

5816

7270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

830

1660

2490

3320

4150

<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:

0.689

Hom.:

10131

Bravo

AF:

0.723

TwinsUK

AF:

0.635

AC:

2356

ALSPAC

AF:

0.645

AC:

2487

ESP6500AA

AF:

0.889

AC:

2249

ESP6500EA

AF:

0.734

AC:

3848

ExAC

AF:

0.496

AC:

19497

Asia WGS

AF:

0.818

AC:

2834

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Oct 29, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25765001)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.4

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.0027

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.14

MetaRNN

Benign

7.2e-7

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.69

PhyloP100

-0.051

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.080

REVEL

Benign

0.010

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.064

MPC

0.50

ClinPred

0.010

GERP RS

1.8

PromoterAI

0.099

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.034

gMVP

0.15

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over