Genetic Variant NM_004957.6:c.28G>T (chr9-127802952-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004957.6(FPGS):c.28G>T(p.Ala10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.806

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05773008).

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.28G>T	p.Ala10Ser	missense	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.28G>T	p.Ala10Ser	missense	Exon 1 of 14	NP_001275732.1	Q05932-4
FPGS	NR_110170.1		n.95G>T		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.28G>T	p.Ala10Ser	missense	Exon 1 of 15	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.35G>T		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000910448.1		c.28G>T	p.Ala10Ser	missense	Exon 1 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1259278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

616202

African (AFR)

AF:

0.00

AC:

AN:

24784

American (AMR)

AF:

0.00

AC:

AN:

16162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20092

East Asian (EAS)

AF:

0.00

AC:

AN:

27488

South Asian (SAS)

AF:

0.00

AC:

AN:

63232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3668

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1020888

Other (OTH)

AF:

0.00

AC:

AN:

51802

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.095

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.011

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.61

M_CAP

Benign

0.053

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.81

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.010

REVEL

Benign

0.022

Sift

Benign

0.67

Sift4G

Benign

0.65

Polyphen

0.0050

Vest4

0.15

MutPred

0.37

Gain of phosphorylation at A10 (P = 0.0323)

MVP

0.18

MPC

0.56

ClinPred

0.055

GERP RS

1.0

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.052

gMVP

0.34

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over