11-112226468-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000317.3(PTS):c.25C>T(p.Arg9Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,804 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTS NM_000317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000317.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-112226469-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552463.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTS	NM_000317.3	c.25C>T	p.Arg9Cys	missense_variant	1/6	ENST00000280362.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTS	ENST00000280362.8	c.25C>T	p.Arg9Cys	missense_variant	1/6	1	NM_000317.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1428804 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707384

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 05, 2021

Variant summary: PTS c.25C>T (p.Arg9Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 192406 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.25C>T, has been reported in the literature in a compound heterozygous individual affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (Leuzzi_2009, Manti_2020), this individual carried a reportedly pathogenic missense variant in trans, and was reported to have PTS enzyme deficiency, measured in patient derived cells (Leuzzi_2009). At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that this variant doesn't affect homodimerization of the PTS enzyme (Das_2014), however, these results do not allow any conclusions about the variant effect on enzyme activity. Another missense variant affecting the same residue (c.26G>A (p. Arg9His)) was reported in affected individuals (HGMD), supporting a potential functional role for this residue in protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.78	N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.017	B;.
Vest4		0.44
MutPred		0.89		Loss of MoRF binding (P = 0.0016);Loss of MoRF binding (P = 0.0016);
MVP		0.95
MPC		0.40
ClinPred		0.26	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.41
gMVP		0.73

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: rs1859865664; hg19: chr11-112097191;