dbSNP rs1008651151: FPGS:p.Arg5Arg (chr9-127802937-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_004957.6(FPGS):c.13C>A(p.Arg5Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000805 in 1,242,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 29)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

FPGS
NM_004957.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.360

Publications

0 publications found

Variant links:

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]

FPGS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP7

Synonymous conserved (PhyloP=0.36 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FPGS	NM_004957.6	MANE Select	c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 15	NP_004948.4
FPGS	NM_001288803.1		c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 14	NP_001275732.1	Q05932-4
FPGS	NR_110170.1		n.80C>A		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FPGS	ENST00000373247.7	TSL:1 MANE Select	c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 15	ENSP00000362344.2	Q05932-1
FPGS	ENST00000460181.5	TSL:1	n.20C>A		non_coding_transcript_exon	Exon 1 of 15
FPGS	ENST00000910448.1		c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.05e-7

AC:

AN:

1242020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

606248

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

24384

American (AMR)

AF:

0.00

AC:

AN:

13948

Ashkenazi Jewish (ASJ)

AF:

0.0000525

AC:

AN:

19034

East Asian (EAS)

AF:

0.00

AC:

AN:

27276

South Asian (SAS)

AF:

0.00

AC:

AN:

59956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3576

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1012444

Other (OTH)

AF:

0.00

AC:

AN:

51032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

9.5

(source)

DANN

Benign

0.58

PhyloP100

0.36

PromoterAI

0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over