rs7856096

Positions:

• chr9-127804260-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004957.6(FPGS):​c.139-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,611,018 control chromosomes in the GnomAD database, including 1,841 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.069 (865 hom., cov: 32)
  • Exomes 𝑓: 0.021 (976 hom.)
• Consequence: FPGS NM_004957.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00700

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: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FPGS	NM_004957.6	c.139-25A>G		intron_variant		ENST00000373247.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FPGS	ENST00000373247.7	c.139-25A>G		intron_variant		1	NM_004957.6	P1

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10498 AN: 152150 Hom.: 860 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0554

GnomAD3 exomes AF: 0.0321 AC: 7952 AN: 247996 Hom.: 416 AF XY: 0.0284 AC XY: 3808 AN XY: 133990

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.00565

Gnomad EAS exome AF: 0.00163

Gnomad SAS exome AF: 0.0317

Gnomad FIN exome AF: 0.0393

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0211 AC: 30717 AN: 1458750 Hom.: 976 Cov.: 32 AF XY: 0.0207 AC XY: 14996 AN XY: 725492

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.00534

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.0323

Gnomad4 FIN exome AF: 0.0382

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0691 AC: 10522 AN: 152268 Hom.: 865 Cov.: 32 AF XY: 0.0687 AC XY: 5114 AN XY: 74456

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0367

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0228 Hom.: 218

Bravo AF: 0.0746

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	11
DANN	Benign	0.58
BranchPoint Hunter		3.0
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: rs7856096; hg19: chr9-130566539;