rs189365250

Positions:

chr11-112233429-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000317.3(PTS):c.315-3T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004008

Clinical Significance

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

Conservation

PhyloP100: 0.547

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 532010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112233429-T-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTS	NM_000317.3 linkuse as main transcript	c.315-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000280362.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTS	ENST00000280362.8 linkuse as main transcript	c.315-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000317.3	P1

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

GnomAD3 exomes

AF:

0.00356

AC:

877

AN:

246582

Hom.:

AF XY:

0.00337

AC XY:

451

AN XY:

133738

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 SAS exome

AF:

0.000271

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

Gnomad4 AFR exome

AF:

0.000872

Gnomad4 AMR exome

AF:

0.00328

Gnomad4 ASJ exome

AF:

0.00219

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000283

Gnomad4 FIN exome

AF:

0.0120

Gnomad4 NFE exome

AF:

0.00493

Gnomad4 OTH exome

AF:

0.00359

GnomAD4 genome

AF:

0.00414

AC:

631

AN:

152306

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00627

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0131

Gnomad4 NFE

AF:

0.00491

Gnomad4 OTH

AF:

0.00520

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

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PTS: BP4, BS2 -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.5

DANN

Benign

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over