chr11-112228687-T-C

Variant names:

• chr11-112228687-T-C
• rs3819331
• ENST00000525645.1:n.252T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000525645.1(PTS):​n.252T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,600,344 control chromosomes in the GnomAD database, including 21,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1451 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19881 hom.)
• Consequence: PTS ENST00000525645.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.186
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-112228687-T-C is Benign according to our data. Variant chr11-112228687-T-C is described in ClinVar as Benign. ClinVar VariationId is 302498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTS	NM_000317.3	c.163+14T>C		intron_variant	Intron 2 of 5	ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8	c.163+14T>C		intron_variant	Intron 2 of 5	1	NM_000317.3	ENSP00000280362.3

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18147 AN: 151806 Hom.: 1445 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.166 AC: 41463 AN: 249736 AF XY: 0.174

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.155 AC: 224757 AN: 1448424 Hom.: 19881 Cov.: 30 AF XY: 0.160 AC XY: 115644 AN XY: 721378

African (AFR) AF: 0.0202 AC: 669 AN: 33192

American (AMR) AF: 0.129 AC: 5765 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3538 AN: 26060

East Asian (EAS) AF: 0.225 AC: 8922 AN: 39600

South Asian (SAS) AF: 0.320 AC: 27459 AN: 85844

European-Finnish (FIN) AF: 0.142 AC: 7487 AN: 52728

Middle Eastern (MID) AF: 0.100 AC: 576 AN: 5746

European-Non Finnish (NFE) AF: 0.146 AC: 161137 AN: 1100632

Other (OTH) AF: 0.153 AC: 9204 AN: 59968

GnomAD4 genome AF: 0.120 AC: 18160 AN: 151920 Hom.: 1451 Cov.: 32 AF XY: 0.124 AC XY: 9224 AN XY: 74234

African (AFR) AF: 0.0282 AC: 1170 AN: 41464

American (AMR) AF: 0.127 AC: 1937 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3468

East Asian (EAS) AF: 0.258 AC: 1331 AN: 5156

South Asian (SAS) AF: 0.344 AC: 1653 AN: 4810

European-Finnish (FIN) AF: 0.140 AC: 1470 AN: 10504

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.144 AC: 9768 AN: 67944

Other (OTH) AF: 0.118 AC: 248 AN: 2110

Alfa AF: 0.140 Hom.: 3101

Bravo AF: 0.110

Asia WGS AF: 0.281 AC: 978 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.5
DANN	Benign	0.81
PhyloP100		0.19
PromoterAI		-0.0062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs3819331; hg19: chr11-112099410; COSMIC: COSV54785665; COSMIC: COSV54785665;