chr11-112233429-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000317.3(PTS):c.315-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,609,882 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 22 hom. )

Consequence

PTS
NM_000317.3 splice_region, intron

Scores

Splicing: ADA: 0.00004008

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.547

Publications

0 publications found

Variant links:

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)

PTS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 11-112233429-T-C is Benign according to our data. Variant chr11-112233429-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 532010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00414 (631/152306) while in subpopulation AMR AF = 0.00627 (96/15302). AF 95% confidence interval is 0.00526. There are 2 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTS	NM_000317.3 link	c.315-3T>C		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000280362.8	NP_000308.1	Q03393

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8 link	c.315-3T>C		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_000317.3	ENSP00000280362.3		Q03393

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

632

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0131

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00492

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00356

AC:

877

AN:

246582

AF XY:

0.00337

show subpopulations

Gnomad AFR exome

AF:

0.000778

Gnomad AMR exome

AF:

0.00305

Gnomad ASJ exome

AF:

0.00201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0120

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00317

GnomAD4 exome

AF:

0.00452

AC:

6587

AN:

1457576

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

3150

AN XY:

724686

show subpopulations

African (AFR)

AF:

0.000872

AC:

AN:

33258

American (AMR)

AF:

0.00328

AC:

145

AN:

44232

Ashkenazi Jewish (ASJ)

AF:

0.00219

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.000283

AC:

AN:

84708

European-Finnish (FIN)

AF:

0.0120

AC:

638

AN:

53196

Middle Eastern (MID)

AF:

0.000528

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00493

AC:

5475

AN:

1110560

Other (OTH)

AF:

0.00359

AC:

216

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

323

646

968

1291

1614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00414

AC:

631

AN:

152306

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41558

American (AMR)

AF:

0.00627

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0131

AC:

139

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00491

AC:

334

AN:

68028

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00418

Hom.:

Bravo

AF:

0.00313

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00355

EpiControl

AF:

0.00285

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTS: BP4, BS2 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Benign:2

Jan 30, 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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.5

(source)

DANN

Benign

0.81

PhyloP100

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.022

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over