chr9-130480450-G-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_054012.4(ASS1):c.838+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,870 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_054012.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
- citrullinemia type IInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
- acute neonatal citrullinemia type IInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- adult-onset citrullinemia type IInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASS1 | NM_054012.4 | c.838+1G>T | splice_donor_variant, intron_variant | Intron 11 of 14 | ENST00000352480.10 | NP_446464.1 | ||
ASS1 | NM_000050.4 | c.838+1G>T | splice_donor_variant, intron_variant | Intron 12 of 15 | NP_000041.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00000797 AC: 2AN: 250802 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461636Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727092 show subpopulations
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74378 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Citrullinemia type I Pathogenic:2
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Citrullinemia Pathogenic:1
This sequence change affects a donor splice site in intron 12 of the ASS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASS1 are known to be pathogenic (PMID: 18473344, 19006241). This variant is present in population databases (rs750214431, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with citrullinemia type 1 (PMID: 19006241, 28111830). ClinVar contains an entry for this variant (Variation ID: 555072). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at