NM_000275.3:c.1503+5G>A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_000275.3(OCA2):c.1503+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000427 in 1,614,106 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_000275.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.1503+5G>A | splice_region_variant, intron_variant | Intron 14 of 23 | 1 | NM_000275.3 | ENSP00000346659.3 | |||
OCA2 | ENST00000353809.9 | c.1431+5G>A | splice_region_variant, intron_variant | Intron 13 of 22 | 1 | ENSP00000261276.8 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152144Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727224
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74440
ClinVar
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:3
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not provided Pathogenic:2
This sequence change falls in intron 14 of the OCA2 gene. It does not directly change the encoded amino acid sequence of the OCA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs368124046, gnomAD 0.01%). This variant has been observed in individuals with oculocutaneous albinism (PMID: 24361966, 29345414; internal data). ClinVar contains an entry for this variant (Variation ID: 211768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24361966). For these reasons, this variant has been classified as Pathogenic. -
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Published functional studies demonstrate the use of a cryptic splice donor site within intron 14, with sequencing of aberrant transcript demonstrating it results in a frameshift, starting with codon Glycine 502, changing this amino acid to a Valine residue, and creating a premature Stop codon at position 84 of the new reading frame, denoted p.Gly502ValfsX84 (Rimoldi et al., 2014).; This variant is associated with the following publications: (PMID: 15712365, 10649493, 24361966, 31077556) -
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
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OCA2-related disorder Pathogenic:1
The OCA2 c.1503+5G>A variant is predicted to interfere with splicing. This intronic variant is predicted to weaken the nearby splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). A functional study using RT-PCR analysis confirmed that this variant results in an abnormal mRNA transcript due to splicing errors (Rimoldi et al. 2014. PubMed ID: 24361966). This variant has been reported in multiple individuals with oculocutaneous albinism (Rimoldi et al. 2014. PubMed ID: 24361966; Zhong et al. 2019. PubMed ID: 31077556). Given the evidence, we interpret this variant as pathogenic. -
Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at