11-89191199-C-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000372.5(TYR):c.820-3C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000372.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYR | NM_000372.5 | c.820-3C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000263321.6 | |||
TYR | XM_011542970.3 | c.820-3C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYR | ENST00000263321.6 | c.820-3C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000372.5 | P1 | |||
TYR | ENST00000526139.1 | n.881-3C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250868Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135636
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461058Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726844
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Tyrosinase-negative oculocutaneous albinism Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 20, 2015 | - - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | This variant has been observed in individual(s) with ocular albinism (PMID: 13680365, 31077556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 1 of the TYR gene. It does not directly change the encoded amino acid sequence of the TYR protein. It affects a nucleotide within the consensus splice site. This variant is also known as IVS1-3C>G. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 99582). - |
not provided, no classification provided | literature only | Retina International | - | - - |
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 24, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at