9-127808825-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 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: Likely_benign. The variant received -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.

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.996G>A	p.Arg332Arg	synonymous	Exon 11 of 15	NP_004948.4
	FPGS	NM_001288803.1		c.918G>A	p.Arg306Arg	synonymous	Exon 10 of 14	NP_001275732.1	Q05932-4
	FPGS	NM_001018078.2		c.846G>A	p.Arg282Arg	synonymous	Exon 11 of 15	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.996G>A	p.Arg332Arg	synonymous	Exon 11 of 15	ENSP00000362344.2	Q05932-1
	FPGS	ENST00000460181.5	TSL:1	n.984G>A		non_coding_transcript_exon	Exon 11 of 15
	FPGS	ENST00000373228.5	TSL:5	c.848G>A	p.Gly283Asp	missense	Exon 10 of 13	ENSP00000362325.1	Q5JU23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000291 AC: 5 AN: 171588 AF XY: 0.0000219

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32066

American (AMR) AF: 0.000107 AC: 4 AN: 37238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25252

East Asian (EAS) AF: 0.00 AC: 0 AN: 36562

South Asian (SAS) AF: 0.00 AC: 0 AN: 80094

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000405 AC: 44 AN: 1085956

Other (OTH) AF: 0.00 AC: 0 AN: 58462

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.095
PROVEAN	Benign	0.29	N
REVEL	Benign	0.014
Sift	Benign	0.080	T
Sift4G	Uncertain	0.021	D
Vest4		0.19
MutPred		0.20		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
Mutation Taster		=100/0	polymorphism

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: rs181035766; hg19: chr9-130571104;