Genetic Variant NM_004957.6:c.64A>T (chr9-127802988-A-T) – 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.64A>T(p.Ile22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I22V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0500412).

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>T	p.Ile22Leu	missense	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.64A>T	p.Ile22Leu	missense	Exon 1 of 14	NP_001275732.1
FPGS	NR_110170.1		n.131A>T		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>T	p.Ile22Leu	missense	Exon 1 of 15	ENSP00000362344.2
FPGS	ENST00000460181.5	TSL:1	n.71A>T		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000393706.6	TSL:2	c.64A>T	p.Ile22Leu	missense	Exon 1 of 14	ENSP00000377309.2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000153

AC:

AN:

1311134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

645864

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000385

AC:

AN:

25950

American (AMR)

AF:

0.00

AC:

AN:

23662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22456

East Asian (EAS)

AF:

0.00

AC:

AN:

28602

South Asian (SAS)

AF:

0.00

AC:

AN:

70412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3876

European-Non Finnish (NFE)

AF:

9.54e-7

AC:

AN:

1048636

Other (OTH)

AF:

0.00

AC:

AN:

54258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000659

AC:

AN:

151776

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41370

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67848

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

10131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.8

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0029

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.33

M_CAP

Benign

0.017

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.051

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.17

REVEL

Benign

0.020

Sift

Benign

0.40

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.17

MutPred

0.26

Gain of disorder (P = 0.027)

MVP

0.11

MPC

0.59

ClinPred

0.033

GERP RS

1.8

PromoterAI

-0.049

Neutral

(source)

Varity_R

0.064

gMVP

0.17

Mutation Taster

=99/1

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