11-112233522-T-C

Variant names:

• chr11-112233522-T-C
• rs59731976
• NM_000317.3:c.405T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000317.3(PTS):​c.405T>C​(p.Thr135Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,613,636 control chromosomes in the GnomAD database, including 514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T135T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (255 hom., cov: 32)
  • Exomes 𝑓: 0.010 (259 hom.)
• Consequence: PTS NM_000317.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.408
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-112233522-T-C is Benign according to our data. Variant chr11-112233522-T-C is described in ClinVar as Benign. ClinVar VariationId is 302499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

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.405T>C	p.Thr135Thr	synonymous	Exon 6 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.405T>C	p.Thr135Thr	synonymous	Exon 6 of 6	ENSP00000280362.3
	PTS	ENST00000531673.5	TSL:1	n.*123+289T>C		intron	N/A	ENSP00000433469.1
	PTS	ENST00000524931.1	TSL:3	c.201T>C	p.Thr67Thr	synonymous	Exon 6 of 6	ENSP00000434688.1

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5519 AN: 152114 Hom.: 256 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.0283

GnomAD2 exomes AF: 0.0138 AC: 3459 AN: 250774 AF XY: 0.0119

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00833

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0103 AC: 15114 AN: 1461404 Hom.: 259 Cov.: 31 AF XY: 0.00963 AC XY: 6998 AN XY: 727018

African (AFR) AF: 0.111 AC: 3721 AN: 33466

American (AMR) AF: 0.0147 AC: 659 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00965 AC: 252 AN: 26122

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39628

South Asian (SAS) AF: 0.00166 AC: 143 AN: 86210

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53364

Middle Eastern (MID) AF: 0.0257 AC: 148 AN: 5758

European-Non Finnish (NFE) AF: 0.00832 AC: 9247 AN: 1111776

Other (OTH) AF: 0.0140 AC: 848 AN: 60372

GnomAD4 genome AF: 0.0364 AC: 5537 AN: 152232 Hom.: 255 Cov.: 32 AF XY: 0.0343 AC XY: 2554 AN XY: 74446

African (AFR) AF: 0.110 AC: 4573 AN: 41504

American (AMR) AF: 0.0214 AC: 328 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00751 AC: 511 AN: 68004

Other (OTH) AF: 0.0280 AC: 59 AN: 2110

Alfa AF: 0.0159 Hom.: 48

Bravo AF: 0.0403

Asia WGS AF: 0.00751 AC: 26 AN: 3474

EpiCase AF: 0.00977

EpiControl AF: 0.0107

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (4)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	PTS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.4
DANN	Benign	0.79
PhyloP100		-0.41
Mutation Taster		=96/4	polymorphism (auto)

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: rs59731976; hg19: chr11-112104245;