rs778736284

Variant names:

• chr11-112228588-G-T
• rs778736284
• NM_000317.3:c.84-6G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000317.3(PTS):​c.84-6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTS NM_000317.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005112
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.39
• 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-112228588-G-T is Benign according to our data. Variant chr11-112228588-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 463154.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTS	NM_000317.3	c.84-6G>T		splice_region_variant, intron_variant	Intron 1 of 5	ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8	c.84-6G>T		splice_region_variant, intron_variant	Intron 1 of 5	1	NM_000317.3	ENSP00000280362.3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 128 AN: 120914 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000678

Gnomad ASJ AF: 0.00103

Gnomad EAS AF: 0.000689

Gnomad SAS AF: 0.000521

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000653

Gnomad OTH AF: 0.000614

GnomAD2 exomes AF: 0.00390 AC: 267 AN: 68438 AF XY: 0.00379

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.00796

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.00411

Gnomad FIN exome AF: 0.00649

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.00329

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000634 AC: 777 AN: 1224840 Hom.: 0 Cov.: 33 AF XY: 0.000620 AC XY: 374 AN XY: 602992

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

African (AFR) AF: 0.00247 AC: 65 AN: 26272

American (AMR) AF: 0.0127 AC: 270 AN: 21328

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 38 AN: 19596

East Asian (EAS) AF: 0.000367 AC: 12 AN: 32726

South Asian (SAS) AF: 0.00167 AC: 94 AN: 56258

European-Finnish (FIN) AF: 0.00103 AC: 35 AN: 34094

Middle Eastern (MID) AF: 0.00187 AC: 7 AN: 3734

European-Non Finnish (NFE) AF: 0.000223 AC: 218 AN: 979340

Other (OTH) AF: 0.000738 AC: 38 AN: 51492

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00108 AC: 131 AN: 120968 Hom.: 0 Cov.: 31 AF XY: 0.00125 AC XY: 73 AN XY: 58258

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

African (AFR) AF: 0.00109 AC: 35 AN: 32244

American (AMR) AF: 0.000677 AC: 8 AN: 11814

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 3 AN: 2920

East Asian (EAS) AF: 0.000692 AC: 3 AN: 4334

South Asian (SAS) AF: 0.000783 AC: 3 AN: 3830

European-Finnish (FIN) AF: 0.00623 AC: 41 AN: 6586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.000653 AC: 37 AN: 56648

Other (OTH) AF: 0.000608 AC: 1 AN: 1644

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00143 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Benign:1

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.79
CADD	Benign	0.051
DANN	Benign	0.58
PhyloP100		-1.4
PromoterAI		-0.0048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.096
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: rs778736284; hg19: chr11-112099311; COSMIC: COSV54786091; COSMIC: COSV54786091;