NM_000317.3:c.84-3C>G

Variant names:

• chr11-112228591-C-G
• rs1230781262
• NM_000317.3:c.84-3C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000317.3(PTS):​c.84-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,517,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: PTS NM_000317.3 splice_region, intron
• Scores: Splicing: ADA: 0.9959
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.462
• Publications: 6 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-112228591-C-G is Pathogenic according to our data. Variant chr11-112228591-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 553378.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.84-3C>G		splice_region intron	N/A	NP_000308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTS	ENST00000280362.8	TSL:1 MANE Select	c.84-3C>G		splice_region intron	N/A	ENSP00000280362.3
	PTS	ENST00000525645.1	TSL:1	n.159-3C>G		splice_region intron	N/A
	PTS	ENST00000531673.5	TSL:1	n.84-3C>G		splice_region intron	N/A	ENSP00000433469.1

Frequencies

GnomAD3 genomes AF: 0.0000227 AC: 3 AN: 132312 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000479

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 190752 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000938 AC: 13 AN: 1385190 Hom.: 0 Cov.: 33 AF XY: 0.0000102 AC XY: 7 AN XY: 688968

African (AFR) AF: 0.00 AC: 0 AN: 30130

American (AMR) AF: 0.00 AC: 0 AN: 33582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24350

East Asian (EAS) AF: 0.00 AC: 0 AN: 38706

South Asian (SAS) AF: 0.00 AC: 0 AN: 77352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4484

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1078328

Other (OTH) AF: 0.00 AC: 0 AN: 57464

GnomAD4 genome AF: 0.0000227 AC: 3 AN: 132312 Hom.: 0 Cov.: 31 AF XY: 0.0000158 AC XY: 1 AN XY: 63368

African (AFR) AF: 0.00 AC: 0 AN: 34968

American (AMR) AF: 0.00 AC: 0 AN: 12760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3236

East Asian (EAS) AF: 0.00 AC: 0 AN: 4624

South Asian (SAS) AF: 0.00 AC: 0 AN: 4310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.0000479 AC: 3 AN: 62624

Other (OTH) AF: 0.00 AC: 0 AN: 1814

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (7)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.54
PhyloP100		0.46
PromoterAI		-0.0040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.54		Position offset: 3

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

Other links and lift over

dbSNP: rs1230781262; hg19: chr11-112099314;