rs797046081
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000372.5(TYR):āc.1234C>Gā(p.Pro412Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000372.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYR | NM_000372.5 | c.1234C>G | p.Pro412Ala | missense_variant | 4/5 | ENST00000263321.6 | |
TYR | XM_011542970.3 | c.1234C>G | p.Pro412Ala | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYR | ENST00000263321.6 | c.1234C>G | p.Pro412Ala | missense_variant | 4/5 | 1 | NM_000372.5 | P1 | |
TYR | ENST00000528243.1 | n.232C>G | non_coding_transcript_exon_variant | 2/3 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1459938Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726322
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Tyrosinase-negative oculocutaneous albinism Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 04, 2015 | - - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 412 of the TYR protein (p.Pro412Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 13680365). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212521). 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 TYR protein function with a positive predictive value of 80%. This variant disrupts the p.Pro412 amino acid residue in TYR. Other variant(s) that disrupt this residue have been observed in individuals with TYR-related conditions (PMID: 30791930, 31077556), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 19, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at