chr9-127808359-C-T

Variant names:

• chr9-127808359-C-T
• rs41307463
• NM_004957.6:c.822+48C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

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.822+48C>T		intron	N/A	NP_004948.4
	FPGS	NM_001288803.1		c.744+48C>T		intron	N/A	NP_001275732.1	Q05932-4
	FPGS	NM_001018078.2		c.672+48C>T		intron	N/A	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.822+48C>T		intron	N/A	ENSP00000362344.2	Q05932-1
	FPGS	ENST00000460181.5	TSL:1	n.810+48C>T		intron	N/A
	FPGS	ENST00000910448.1		c.924+48C>T		intron	N/A	ENSP00000580507.1

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

GnomAD2 exomes AF: 0.0181 AC: 4528 AN: 249952 AF XY: 0.0183

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 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

African (AFR) AF: 0.00424 AC: 137 AN: 32304

American (AMR) AF: 0.0140 AC: 623 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 819 AN: 25740

East Asian (EAS) AF: 0.0000762 AC: 3 AN: 39370

South Asian (SAS) AF: 0.0142 AC: 1207 AN: 85096

European-Finnish (FIN) AF: 0.00719 AC: 383 AN: 53292

Middle Eastern (MID) AF: 0.0216 AC: 123 AN: 5682

European-Non Finnish (NFE) AF: 0.0250 AC: 26515 AN: 1062178

Other (OTH) AF: 0.0206 AC: 1208 AN: 58504

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

African (AFR) AF: 0.00448 AC: 186 AN: 41522

American (AMR) AF: 0.0215 AC: 328 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4820

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1707 AN: 68014

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.3
DANN	Benign	0.80
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs41307463; hg19: chr9-130570638;