rs778053171

Variant names:

• chr11-112230626-A-C
• rs778053171
• NM_000317.3:c.187A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-112230626-A-C
• chr11-112230626-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000317.3(PTS):​c.187A>C​(p.Ile63Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. I63V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTS NM_000317.3 missense, splice_region
• Scores: Splicing: ADA: 0.007028
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 0 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-112230626-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 551578.Status of the report is criteria_provided_single_submitter, 1 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTS	NM_000317.3	MANE Select	c.187A>C	p.Ile63Leu	missense splice_region	Exon 4 of 6	NP_000308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTS	ENST00000280362.8	TSL:1 MANE Select	c.187A>C	p.Ile63Leu	missense splice_region	Exon 4 of 6	ENSP00000280362.3
	PTS	ENST00000531673.5	TSL:1	n.164A>C		splice_region non_coding_transcript_exon	Exon 3 of 7	ENSP00000433469.1
	PTS	ENST00000524931.1	TSL:3	c.-18A>C		splice_region	Exon 4 of 6	ENSP00000434688.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456000 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724760

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106734

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.13
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.60
Sift	Benign	0.056	T
Sift4G	Benign	0.061	T
Polyphen		0.031	B
Vest4		0.54
MutPred		0.48		Loss of catalytic residue at P65 (P = 0.0303)
MVP		0.98
MPC		0.34
ClinPred		0.82	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.72
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0070
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.010		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: rs778053171; hg19: chr11-112101349;