rs62508613

Positions:

• chr12-102843629-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000277.3(PAH):​c.1199+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 0.586

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-102843629-C-T is Pathogenic according to our data. Variant chr12-102843629-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102843629-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1199+17G>A		intron_variant		ENST00000553106.6
PAH	NM_001354304.2	c.1199+17G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1199+17G>A		intron_variant		1	NM_000277.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461242 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74180

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phenylketonuria Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Unidade de Bioquimica Genetica, Centro Hospitalar do Porto	Nov 10, 2017	The variant was observed in four patients, two with a diagnosis of phenylketonuria (PKU) and the other two with a diagnosis of mild hyperphenylalaninemia (MHP). In the two PKU patients, the variant was found in compound heterozygosity with IVS10-11G>A (c.1066-11G>A), in intron 10, and c.250G>T (p.D84Y), in exon 3. Meanwhile, in the two MHP patients, it was found with IVS2+5G>C (c.168+5G>C), in intron 2, and c.754C>T (p.R252W), in exon 7. In silico analysis in Human Splicing Finder showed that it activates an intronic cryptic acceptor site, which potentially alters splicing. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 01, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in skipping of exon 11 (PMID: 29684050). ClinVar contains an entry for this variant (Variation ID: 102555). This variant is also known as IVS11+17G>A. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 11139255, 30829006; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 17, 2018	- -

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2023	Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11139255, 31589614, 32668217, 30829006, 29684050) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PAH: PM3:Very Strong, PM2, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs62508613; hg19: chr12-103237407;