rs41307463

chr9-127808359-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004957.6(FPGS):c.822+48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,558,978 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (36 hom., cov: 32)
  • Exomes 𝑓: 0.022 (408 hom.)
• Consequence: FPGS NM_004957.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.540

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2504/152192) while in subpopulation NFE AF= 0.0251 (1707/68014). AF 95% confidence interval is 0.0241. There are 36 homozygotes in gnomad4. There are 1129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FPGS	NM_004957.6	c.822+48C>T		intron_variant		ENST00000373247.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FPGS	ENST00000373247.7	c.822+48C>T		intron_variant		1	NM_004957.6	P1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2506 AN: 152074 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0181 AC: 4528 AN: 249952 Hom.: 65 AF XY: 0.0183 AC XY: 2479 AN XY: 135240

Gnomad AFR exome AF: 0.00390

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0341

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.00695

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0220 AC: 31018 AN: 1406786 Hom.: 408 Cov.: 23 AF XY: 0.0220 AC XY: 15445 AN XY: 702944

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0318

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.00719

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0165 AC: 2504 AN: 152192 Hom.: 36 Cov.: 32 AF XY: 0.0152 AC XY: 1129 AN XY: 74410

Gnomad4 AFR AF: 0.00448

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0251

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0215 Hom.: 6

Bravo AF: 0.0169

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	1.3
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs41307463; hg19: chr9-130570638;