chr16-28477542-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001042432.2(CLN3):c.1291C>T(p.His431Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,744 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H431H) has been classified as Likely benign.
Frequency
Consequence
NM_001042432.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.1291C>T | p.His431Tyr | missense_variant | 16/16 | ENST00000636147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.1291C>T | p.His431Tyr | missense_variant | 16/16 | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251108Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135734
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461500Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727024
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2021 | This sequence change replaces histidine with tyrosine at codon 431 of the CLN3 protein (p.His431Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs759510380, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with CLN3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at