11-112226517-G-A

Position:

• chr11-112226517-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000317.3(PTS):​c.74G>A​(p.Arg25Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,430,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PTS NM_000317.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.22

Genes affected

PTS (HGNC:9689): (6-pyruvoyltetrahydropterin synthase) The enzyme encoded by this gene catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin from GTP. Tetrahydrobiopterin, also known as BH(4), is an essential cofactor and regulator of various enzyme activities, including enzymes involved in serotonin biosynthesis and NO synthase activity. Mutations in this gene result in hyperphenylalaninemia. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a chain 6-pyruvoyl tetrahydrobiopterin synthase (size 144) in uniprot entity PTPS_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000317.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-112226517-G-A is Pathogenic according to our data. Variant chr11-112226517-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTS	NM_000317.3	c.74G>A	p.Arg25Gln	missense_variant	1/6	ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8	c.74G>A	p.Arg25Gln	missense_variant	1/6	1	NM_000317.3	ENSP00000280362	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430606 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1994	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 09, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg25 amino acid residue in PTS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23138986, 9450907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects PTS protein function (PMID: 8178819). This variant has been observed in individual(s) with biopterin-deficient hyperphenylalaninemia (PMID: 8178819). ClinVar contains an entry for this variant (Variation ID: 476). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 25 of the PTS protein (p.Arg25Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.60
MutPred		0.95		Loss of MoRF binding (P = 0.0264);Loss of MoRF binding (P = 0.0264);
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.83

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: rs104894273; hg19: chr11-112097240;