chr9-127802988-A-T

Variant names:

• chr9-127802988-A-T
• rs10760502
• NM_004957.6:c.64A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004957.6(FPGS):​c.64A>T​(p.Ile22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. I22V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510
• Publications: 40 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0500412).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	NM_004957.6	MANE Select	c.64A>T	p.Ile22Leu	missense	Exon 1 of 15	NP_004948.4
	FPGS	NM_001288803.1		c.64A>T	p.Ile22Leu	missense	Exon 1 of 14	NP_001275732.1
	FPGS	NR_110170.1		n.131A>T		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	ENST00000373247.7	TSL:1 MANE Select	c.64A>T	p.Ile22Leu	missense	Exon 1 of 15	ENSP00000362344.2
	FPGS	ENST00000460181.5	TSL:1	n.71A>T		non_coding_transcript_exon	Exon 1 of 15
	FPGS	ENST00000393706.6	TSL:2	c.64A>T	p.Ile22Leu	missense	Exon 1 of 14	ENSP00000377309.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000153 AC: 2 AN: 1311134 Hom.: 0 Cov.: 56 AF XY: 0.00 AC XY: 0 AN XY: 645864

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000385 AC: 1 AN: 25950

American (AMR) AF: 0.00 AC: 0 AN: 23662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22456

East Asian (EAS) AF: 0.00 AC: 0 AN: 28602

South Asian (SAS) AF: 0.00 AC: 0 AN: 70412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3876

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1048636

Other (OTH) AF: 0.00 AC: 0 AN: 54258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74092

African (AFR) AF: 0.0000242 AC: 1 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67848

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 10131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.8
DANN	Benign	0.82
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.051
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.020
Sift	Benign	0.40	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.26		Gain of disorder (P = 0.027)
MVP		0.11
MPC		0.59
ClinPred		0.033	T
GERP RS		1.8
PromoterAI		-0.049	Neutral
Varity_R		0.064
gMVP		0.17
Mutation Taster		=99/1	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: rs10760502; hg19: chr9-130565267;