11-112226508-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000317.3(PTS):ā€‹c.65C>Gā€‹(p.Ala22Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,432,042 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 (no stars).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

PTS
NM_000317.3 missense

Scores

11
7
1

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.94
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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, 0.991
PP5
Variant 11-112226508-C-G is Pathogenic according to our data. Variant chr11-112226508-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1679199.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTSNM_000317.3 linkc.65C>G p.Ala22Gly missense_variant 1/6 ENST00000280362.8 NP_000308.1 Q03393

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTSENST00000280362.8 linkc.65C>G p.Ala22Gly missense_variant 1/61 NM_000317.3 ENSP00000280362.3 Q03393

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000209
AC:
3
AN:
1432042
Hom.:
0
Cov.:
31
AF XY:
0.00000282
AC XY:
2
AN XY:
709192
show subpopulations
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:
0.0000245
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.09e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingMedical Genetics Research Center, Mashhad University of Medical SciencesDec 30, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.3
M;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.011
D;D
Polyphen
1.0
D;.
Vest4
0.78
MutPred
0.96
Loss of catalytic residue at A22 (P = 0.0651);Loss of catalytic residue at A22 (P = 0.0651);
MVP
1.0
MPC
0.99
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.94
gMVP
0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-112097231; API