12-102912888-T-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting
The NM_000277.3(PAH):āc.71A>Gā(p.Tyr24Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,607,848 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y24Y) has been classified as Likely benign.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.71A>G | p.Tyr24Cys | missense_variant | 2/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.71A>G | p.Tyr24Cys | missense_variant | 3/14 | ||
PAH | XM_017019370.2 | c.71A>G | p.Tyr24Cys | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.71A>G | p.Tyr24Cys | missense_variant | 2/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000985 AC: 15AN: 152234Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000219 AC: 55AN: 251378Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135854
GnomAD4 exome AF: 0.000139 AC: 203AN: 1455496Hom.: 3 Cov.: 29 AF XY: 0.000189 AC XY: 137AN XY: 724606
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152352Hom.: 1 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74514
ClinVar
Submissions by phenotype
Phenylketonuria Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the PAH protein (p.Tyr24Cys). This variant is present in population databases (rs539994406, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 458080). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at