rs17855900

Variant names:

• chr9-127813306-C-T
• rs17855900
• NM_004957.6:c.1466C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004957.6(FPGS):​c.1466C>T​(p.Ala489Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.230

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031234622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6	c.1466C>T	p.Ala489Val	missense_variant	Exon 15 of 15	ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7	c.1466C>T	p.Ala489Val	missense_variant	Exon 15 of 15	1	NM_004957.6	ENSP00000362344.2

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00114 AC: 284 AN: 249744 Hom.: 1 AF XY: 0.000954 AC XY: 129 AN XY: 135290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0152

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1460728 Hom.: 1 Cov.: 30 AF XY: 0.000252 AC XY: 183 AN XY: 726658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00816

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000505 AC: 77 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000959 Hom.: 1

Bravo AF: 0.000627

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.5
DANN	Benign	0.97
DEOGEN2	Benign	0.17	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0070	B;B;.
Vest4		0.11
MVP		0.42
MPC		0.65
ClinPred		0.019	T
GERP RS		1.4
Varity_R		0.035
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs17855900; hg19: chr9-130575585; COSMIC: COSV61229682; COSMIC: COSV61229682;