9-127804260-A-G

Variant names:

• chr9-127804260-A-G
• rs7856096
• NM_004957.6:c.139-25A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 rank	MANE	Protein	UniProt
FPGS	NM_004957.6	c.139-25A>G		intron_variant	Intron 1 of 14	ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7	c.139-25A>G		intron_variant	Intron 1 of 14	1	NM_004957.6	ENSP00000362344.2

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

GnomAD2 exomes AF: 0.0321 AC: 7952 AN: 247996 AF XY: 0.0284

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 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

African (AFR) AF: 0.197 AC: 6578 AN: 33454

American (AMR) AF: 0.0207 AC: 922 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00534 AC: 138 AN: 25822

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39684

South Asian (SAS) AF: 0.0323 AC: 2769 AN: 85780

European-Finnish (FIN) AF: 0.0382 AC: 2034 AN: 53202

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5758

European-Non Finnish (NFE) AF: 0.0149 AC: 16594 AN: 1110286

Other (OTH) AF: 0.0257 AC: 1548 AN: 60276

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

African (AFR) AF: 0.198 AC: 8206 AN: 41528

American (AMR) AF: 0.0309 AC: 472 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5180

South Asian (SAS) AF: 0.0367 AC: 177 AN: 4822

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0160 AC: 1090 AN: 68034

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0318 Hom.: 966

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
PhyloP100		-0.0070
BranchPoint Hunter		3.0
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: rs7856096; hg19: chr9-130566539;