9-127802988-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004957.6(FPGS):c.64A>G(p.Ile22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,461,332 control chromosomes in the GnomAD database, including 331,092 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.73 (41171 hom., cov: 31)
  • Exomes 𝑓: 0.66 (289921 hom.)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0510

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.226459E-7).
• BP6: Variant 9-127802988-A-G is Benign according to our data. Variant chr9-127802988-A-G is described in ClinVar as [Benign]. Clinvar id is 1232138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FPGS	NM_004957.6	c.64A>G	p.Ile22Val	missense_variant	1/15	ENST00000373247.7
FPGS	NM_001288803.1	c.64A>G	p.Ile22Val	missense_variant	1/14
FPGS	XM_005251864.5	c.64A>G	p.Ile22Val	missense_variant	1/16
FPGS	NR_110170.1	n.131A>G		non_coding_transcript_exon_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FPGS	ENST00000373247.7	c.64A>G	p.Ile22Val	missense_variant	1/15	1	NM_004957.6	P1

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110439 AN: 151712 Hom.: 41131 Cov.: 31

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.783

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.683

GnomAD3 exomes AF: 0.638 AC: 42882 AN: 67242 Hom.: 14001 AF XY: 0.639 AC XY: 25003 AN XY: 39114

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.956

Gnomad SAS exome AF: 0.654

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.597

GnomAD4 exome AF: 0.662 AC: 866421 AN: 1309512 Hom.: 289921 Cov.: 56 AF XY: 0.662 AC XY: 426723 AN XY: 645006

Gnomad4 AFR exome AF: 0.861

Gnomad4 AMR exome AF: 0.601

Gnomad4 ASJ exome AF: 0.575

Gnomad4 EAS exome AF: 0.970

Gnomad4 SAS exome AF: 0.671

Gnomad4 FIN exome AF: 0.773

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.662

GnomAD4 genome AF: 0.728 AC: 110528 AN: 151820 Hom.: 41171 Cov.: 31 AF XY: 0.731 AC XY: 54217 AN XY: 74176

Gnomad4 AFR AF: 0.858

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.966

Gnomad4 SAS AF: 0.690

Gnomad4 FIN AF: 0.783

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.680

Alfa AF: 0.654 Hom.: 3690

Bravo AF: 0.723

TwinsUK AF: 0.635 AC: 2356

ALSPAC AF: 0.645 AC: 2487

ESP6500AA AF: 0.889 AC: 2249

ESP6500EA AF: 0.734 AC: 3848

ExAC AF: 0.496 AC: 19497

Asia WGS AF: 0.818 AC: 2834 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

This variant is associated with the following publications: (PMID: 25765001) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.4
Dann	Benign	0.55
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.14	T;T;T;.
MetaRNN	Benign	7.2e-7	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.080	N;.;N;N
REVEL	Benign	0.010
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.064
MPC		0.50
ClinPred		0.010	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.034
gMVP		0.15

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: rs10760502; hg19: chr9-130565267; COSMIC: COSV64675315; COSMIC: COSV64675315;