rs1859865574

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_000317.3(PTS):c.22C>G(p.Arg8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,428,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R8C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PTS
NM_000317.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.10

Publications

0 publications found

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]

PTS Gene-Disease associations (from GenCC):

BH4-deficient hyperphenylalaninemia A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

PTS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000317.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.12554 (below the threshold of 3.09). Trascript score misZ: -0.18308 (below the threshold of 3.09). GenCC associations: The gene is linked to BH4-deficient hyperphenylalaninemia A.

BP4

Computational evidence support a benign effect (MetaRNN=0.17435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTS	NM_000317.3	MANE Select	c.22C>G	p.Arg8Gly	missense	Exon 1 of 6	NP_000308.1	Q03393

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTS	ENST00000280362.8	TSL:1 MANE Select	c.22C>G	p.Arg8Gly	missense	Exon 1 of 6	ENSP00000280362.3	Q03393
PTS	ENST00000525645.1	TSL:1	n.97C>G		non_coding_transcript_exon	Exon 1 of 2
PTS	ENST00000531673.5	TSL:1	n.22C>G		non_coding_transcript_exon	Exon 1 of 7	ENSP00000433469.1	E9PKY8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1428720

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.00

AC:

AN:

37558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25390

East Asian (EAS)

AF:

0.00

AC:

AN:

38600

South Asian (SAS)

AF:

0.00

AC:

AN:

81454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49738

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1097702

Other (OTH)

AF:

0.00

AC:

AN:

59372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Benign

1.0

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.36

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.42

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.17

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

-0.52

PhyloP100

-1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

REVEL

Benign

0.19

Sift

Benign

0.27

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.11

MutPred

0.70

Loss of MoRF binding (P = 0.0076)

MVP

0.70

MPC

0.37

ClinPred

0.055

GERP RS

-1.8

PromoterAI

0.021

Neutral

(source)

Varity_R

0.38

gMVP

0.68

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over