rs1167104933

Variant names:

• chr11-112226516-C-G
• rs1167104933
• NM_000317.3:c.73C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-112226516-C-G
• chr11-112226516-C-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000317.3(PTS):​c.73C>G​(p.Arg25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,952 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25Q) has been classified 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:5
• Conservation: PhyloP100: 1.77
• Publications: 7 publications found

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 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, 4 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 chr11-112226517-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 11-112226516-C-G is Pathogenic according to our data. Variant chr11-112226516-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 463153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.73C>G	p.Arg25Gly	missense	Exon 1 of 6	NP_000308.1	Q03393

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTS	ENST00000280362.8	TSL:1 MANE Select	c.73C>G	p.Arg25Gly	missense	Exon 1 of 6	ENSP00000280362.3	Q03393
	PTS	ENST00000525645.1	TSL:1	n.148C>G		non_coding_transcript_exon	Exon 1 of 2
	PTS	ENST00000531673.5	TSL:1	n.73C>G		non_coding_transcript_exon	Exon 1 of 7	ENSP00000433469.1	E9PKY8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000102 AC: 2 AN: 195620 AF XY: 0.00000950

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000136

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430952 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708570

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 37798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38680

South Asian (SAS) AF: 0.00 AC: 0 AN: 81482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098984

Other (OTH) AF: 0.00 AC: 0 AN: 59486

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		1.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.94		Loss of MoRF binding (P = 0.0152)
MVP		1.0
MPC		0.83
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		0.010	Neutral
Varity_R		0.98
gMVP		0.90
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1167104933; hg19: chr11-112097239;