rs104894273

Variant names:

• chr11-112226517-G-A
• rs104894273
• NM_000317.3:c.74G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-112226517-G-A
• chr11-112226517-G-C

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 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 (★★). ClinVar reports functional evidence for this variant: "SCV002230130: Experimental studies have shown that this variant affects PTS protein function (PMID:8178819).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25G) 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:3
• Conservation: PhyloP100: 6.22
• Publications: 9 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002230130: Experimental studies have shown that this variant affects PTS protein function (PMID: 8178819).
• PM1: In a hotspot region, there are 4 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 chr11-112226516-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.
• 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, 0.987
• PP5: Variant 11-112226517-G-A is Pathogenic according to our data. 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.

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.74G>A	p.Arg25Gln	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.74G>A	p.Arg25Gln	missense	Exon 1 of 6	ENSP00000280362.3	Q03393
	PTS	ENST00000525645.1	TSL:1	n.149G>A		non_coding_transcript_exon	Exon 1 of 2
	PTS	ENST00000531673.5	TSL:1	n.74G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000433469.1	E9PKY8

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

African (AFR) AF: 0.00 AC: 0 AN: 33284

American (AMR) AF: 0.00 AC: 0 AN: 37706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 38686

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098770

Other (OTH) AF: 0.00 AC: 0 AN: 59472

GnomAD4 genome Cov.: 31

Alfa AF: 0.000451 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (3)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.95		Loss of MoRF binding (P = 0.0264)
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.097	Neutral
Varity_R		0.83
gMVP		0.83
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894273; hg19: chr11-112097240;