Genetic Variant NM_004957.6:c.19C>T (chr9-127802943-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004957.6(FPGS):c.19C>T(p.His7Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,400,600 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.000026 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

FPGS
NM_004957.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.55

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.112961024).

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.19C>T	p.His7Tyr	missense	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.19C>T	p.His7Tyr	missense	Exon 1 of 14	NP_001275732.1	Q05932-4
FPGS	NR_110170.1		n.86C>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.19C>T	p.His7Tyr	missense	Exon 1 of 15	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.26C>T		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000910448.1		c.19C>T	p.His7Tyr	missense	Exon 1 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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

GnomAD2 exomes

AF:

0.0000329

AC:

AN:

30414

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1248812

Hom.:

Cov.:

AF XY:

0.0000213

AC XY:

AN XY:

610136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24524

American (AMR)

AF:

0.0000678

AC:

AN:

14758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19430

East Asian (EAS)

AF:

0.00

AC:

AN:

27350

South Asian (SAS)

AF:

0.0000164

AC:

AN:

61128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30670

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3612

European-Non Finnish (NFE)

AF:

0.0000157

AC:

AN:

1015978

Other (OTH)

AF:

0.0000973

AC:

AN:

51362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000264

AC:

AN:

151788

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41308

American (AMR)

AF:

0.000262

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000511

AC:

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

0.084

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.022

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.76

M_CAP

Benign

0.056

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

1.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.1

REVEL

Benign

0.054

Sift

Uncertain

0.019

Sift4G

Benign

0.43

Polyphen

0.51

Vest4

0.17

MutPred

0.34

Loss of disorder (P = 0.0276)

MVP

0.30

MPC

0.97

ClinPred

0.10

GERP RS

4.3

PromoterAI

0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.18

gMVP

0.29

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over