rs181035766

Variant names:

• chr9-127808825-G-A
• rs181035766
• NM_004957.6:c.996G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-127808825-G-A
• chr9-127808825-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_004957.6(FPGS):​c.996G>A​(p.Arg332Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,410,844 control chromosomes in the GnomAD database, including 1 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: not found (cov: 32)
  • Exomes 𝑓: 0.000035 (1 hom.)
• Consequence: FPGS NM_004957.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071068466).
• BP7: Synonymous conserved (PhyloP=-0.095 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6	c.996G>A	p.Arg332Arg	synonymous_variant	Exon 11 of 15	ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7	c.996G>A	p.Arg332Arg	synonymous_variant	Exon 11 of 15	1	NM_004957.6	ENSP00000362344.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000291 AC: 5 AN: 171588 Hom.: 1 AF XY: 0.0000219 AC XY: 2 AN XY: 91506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000623

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000347 AC: 49 AN: 1410844 Hom.: 1 Cov.: 32 AF XY: 0.0000330 AC XY: 23 AN XY: 697324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0093	T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.32	T;.;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	0.29	.;N;N
REVEL	Benign	0.014
Sift	Benign	0.080	.;T;T
Sift4G	Uncertain	0.021	D;D;T
Vest4		0.19
MutPred		0.20		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;
MVP		0.28
ClinPred		0.027	T
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs181035766; hg19: chr9-130571104;