Genetic Variant FPGS:p.Ala19Pro (chr9-127802979-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_004957.6(FPGS):c.55G>C(p.Ala19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,310,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A19V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.38

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05412233).

BP6

Variant 9-127802979-G-C is Benign according to our data. Variant chr9-127802979-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3516945.Status of the report is criteria_provided_single_submitter, 1 stars.

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.55G>C	p.Ala19Pro	missense	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.55G>C	p.Ala19Pro	missense	Exon 1 of 14	NP_001275732.1	Q05932-4
FPGS	NR_110170.1		n.122G>C		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FPGS	ENST00000373247.7	TSL:1 MANE Select	c.55G>C	p.Ala19Pro	missense	Exon 1 of 15	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.62G>C		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000910448.1		c.55G>C	p.Ala19Pro	missense	Exon 1 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.63e-7

AC:

AN:

1310734

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

645756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25852

American (AMR)

AF:

0.00

AC:

AN:

23418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22394

East Asian (EAS)

AF:

0.00

AC:

AN:

28644

South Asian (SAS)

AF:

0.00

AC:

AN:

70354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3872

European-Non Finnish (NFE)

AF:

9.53e-7

AC:

AN:

1048868

Other (OTH)

AF:

0.00

AC:

AN:

54286

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

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

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.064

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.3

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0051

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.62

M_CAP

Benign

0.026

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-1.4

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.010

REVEL

Benign

0.016

Sift

Benign

0.30

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.029

MutPred

0.45

Loss of helix (P = 3e-04)

MVP

0.17

MPC

0.78

ClinPred

0.045

GERP RS

-2.1

PromoterAI

-0.033

Neutral

(source)

Varity_R

0.11

gMVP

0.27

Mutation Taster

=78/22

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over