3-149221646-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_000096.4(CP):c.146+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000993 in 1,611,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000096.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CP | ENST00000264613.11 | c.146+1G>A | splice_donor_variant, intron_variant | Intron 1 of 18 | 1 | NM_000096.4 | ENSP00000264613.6 | |||
CP | ENST00000490639.5 | n.178+1G>A | splice_donor_variant, intron_variant | Intron 1 of 16 | 1 | |||||
CP | ENST00000455472.3 | c.146+1G>A | splice_donor_variant, intron_variant | Intron 1 of 3 | 5 | ENSP00000426888.1 | ||||
CP | ENST00000481169.5 | n.146+1G>A | splice_donor_variant, intron_variant | Intron 1 of 17 | 2 | ENSP00000418773.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1459318Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7AN XY: 725726
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Deficiency of ferroxidase Pathogenic:1
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not provided Pathogenic:1
Identified in patients with aceruloplasminemia in published literature; this includes one homozgous patient and one patient with c.146+1G>A and a second CP variant but phase was not known (PMID: 34670377); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14742624, 34670377) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at