rs62642094
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4_SupportingPP3PP5_Very_Strong
The NM_000277.3(PAH):c.208_210del(p.Ser70del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PAH
NM_000277.3 inframe_deletion
NM_000277.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.90
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000277.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000277.3. Strenght limited to Supporting due to length of the change: 1aa.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 12-102894876-GAGA-G is Pathogenic according to our data. Variant chr12-102894876-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 102632.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102894876-GAGA-G is described in Lovd as [Pathogenic]. Variant chr12-102894876-GAGA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.208_210del | p.Ser70del | inframe_deletion | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9819_863-9817del | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.208_210del | p.Ser70del | inframe_deletion | 4/14 | ||
PAH | XM_017019370.2 | c.208_210del | p.Ser70del | inframe_deletion | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.208_210del | p.Ser70del | inframe_deletion | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
1
AN:
152068
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251342Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD3 exomes
AF:
AC:
3
AN:
251342
Hom.:
AF XY:
AC XY:
1
AN XY:
135842
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461628Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727132
GnomAD4 exome
AF:
AC:
3
AN:
1461628
Hom.:
AF XY:
AC XY:
2
AN XY:
727132
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74410
GnomAD4 genome
?
AF:
AC:
1
AN:
152186
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74410
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 26, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 05, 2018 | PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, PM3, PS3, PM2, PM4). - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 24, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 14, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 07, 2021 | Variant summary: PAH c.208_210delTCT (p.Ser70del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein that is located in the ACT domain (IPR002912), which proposed to have a regulatory role in protein function (InterPro). The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). c.208_210delTCT has been reported in the literature in several compound heterozygous and homozygous individuals (mostly of East Asian origin) who were affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with reported disease phenotypes ranging from mild hyperphenylalaninemia to classic phenylketonuria (e.g. Okano_1998, Okano_2011, Zhu_2013, Tao_2015, Li_2018, Su_2019, Tao_2021); of note, in the 5 reported homozygous patients a mild PKU phenotype was described (Li_2018, Su_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This variant, c.208_210del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ser70del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62642094, gnomAD 0.006%). This variant has been observed in individual(s) with PAH-related diseases from mild hyperphenylalaninemia to classic phenylketonuria (PMID: 15503242, 16256386, 23271928, 23932990; Invitae). ClinVar contains an entry for this variant (Variation ID: 102632). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
not provided Other:3
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
not provided, flagged submission | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
not provided, flagged submission | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at