chr11-112226445-T-A

Variant names:

• chr11-112226445-T-A
• rs1859865221
• NM_000317.3:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000317.3(PTS):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,426,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTS NM_000317.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.617
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 34 pathogenic variants. Next in-frame start position is after 69 codons. Genomic position: 112230644. Lost 0.468 part of the original CDS.
• PS1: Another start lost variant in NM_000317.3 (PTS) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

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.2T>A	p.Met1?	start_lost	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.2T>A	p.Met1?	start_lost	Exon 1 of 6	ENSP00000280362.3	Q03393
	PTS	ENST00000525645.1	TSL:1	n.77T>A		non_coding_transcript_exon	Exon 1 of 2
	PTS	ENST00000531673.5	TSL:1	n.2T>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000433469.1	E9PKY8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1426856 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.00 AC: 0 AN: 37300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25346

East Asian (EAS) AF: 0.00 AC: 0 AN: 38580

South Asian (SAS) AF: 0.00 AC: 0 AN: 81262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1096624

Other (OTH) AF: 0.00 AC: 0 AN: 59292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.78	D
PhyloP100		0.62
PROVEAN	Benign	-0.36	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.26	T
Polyphen		0.16	B
Vest4		0.88
MutPred		0.95		Gain of MoRF binding (P = 0.0087)
MVP		0.99
ClinPred		0.96	D
GERP RS		3.8
PromoterAI		0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.90
gMVP		0.81
Mutation Taster		=6/194	disease causing

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: rs1859865221; hg19: chr11-112097168;