chr9-127808301-A-G

Variant names:

• chr9-127808301-A-G
• NM_004957.6:c.812A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004957.6(FPGS):​c.812A>G​(p.Gln271Arg) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.661
• Publications: 0 publications found

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]

ACMG classification

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=0.07103145).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	NM_004957.6	MANE Select	c.812A>G	p.Gln271Arg	missense	Exon 9 of 15	NP_004948.4
	FPGS	NM_001288803.1		c.734A>G	p.Gln245Arg	missense	Exon 8 of 14	NP_001275732.1	Q05932-4
	FPGS	NM_001018078.2		c.662A>G	p.Gln221Arg	missense	Exon 9 of 15	NP_001018088.1	Q05932-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	ENST00000373247.7	TSL:1 MANE Select	c.812A>G	p.Gln271Arg	missense	Exon 9 of 15	ENSP00000362344.2	Q05932-1
	FPGS	ENST00000460181.5	TSL:1	n.800A>G		non_coding_transcript_exon	Exon 9 of 15
	FPGS	ENST00000910448.1		c.914A>G	p.Gln305Arg	missense	Exon 10 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.67	N
PhyloP100		0.66
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.013
Sift	Benign	0.52	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.32		Gain of helix (P = 0.2059)
MVP		0.42
MPC		0.64
ClinPred		0.12	T
GERP RS		2.8
Varity_R		0.064
gMVP		0.26
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr9-130570580;