9-127802943-C-A

Variant names:

• chr9-127802943-C-A
• rs760460465
• NM_004957.6:c.19C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004957.6(FPGS):​c.19C>A​(p.His7Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,400,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H7Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10148907).

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.19C>A	p.His7Asn	missense	Exon 1 of 15	NP_004948.4
	FPGS	NM_001288803.1		c.19C>A	p.His7Asn	missense	Exon 1 of 14	NP_001275732.1	Q05932-4
	FPGS	NR_110170.1		n.86C>A		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	ENST00000373247.7	TSL:1 MANE Select	c.19C>A	p.His7Asn	missense	Exon 1 of 15	ENSP00000362344.2	Q05932-1
	FPGS	ENST00000460181.5	TSL:1	n.26C>A		non_coding_transcript_exon	Exon 1 of 15
	FPGS	ENST00000910448.1		c.19C>A	p.His7Asn	missense	Exon 1 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151788 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000240 AC: 3 AN: 1248810 Hom.: 0 Cov.: 33 AF XY: 0.00000492 AC XY: 3 AN XY: 610134

African (AFR) AF: 0.00 AC: 0 AN: 24524

American (AMR) AF: 0.00 AC: 0 AN: 14758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19430

East Asian (EAS) AF: 0.00 AC: 0 AN: 27350

South Asian (SAS) AF: 0.0000491 AC: 3 AN: 61128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1015976

Other (OTH) AF: 0.00 AC: 0 AN: 51362

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151788 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74146

African (AFR) AF: 0.00 AC: 0 AN: 41308

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.61
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.031
Sift	Benign	0.26	T
Sift4G	Benign	0.42	T
Polyphen		0.065	B
Vest4		0.23
MutPred		0.24		Loss of methylation at R5 (P = 0.1052)
MVP		0.26
MPC		0.85
ClinPred		0.17	T
GERP RS		4.3
PromoterAI		0.26	Neutral
Varity_R		0.16
gMVP		0.24
Mutation Taster		=98/2	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: rs760460465; hg19: chr9-130565222;