9-130499504-GCATGAAC-GG
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP5_Moderate
The NM_054012.4(ASS1):c.1128_1134delCATGAACinsG(p.Ser376_Asn378delinsArg) variant causes a missense, conservative inframe deletion, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_054012.4 missense, conservative_inframe_deletion, splice_region
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASS1 | NM_054012.4 | c.1128_1134delCATGAACinsG | p.Ser376_Asn378delinsArg | missense_variant, conservative_inframe_deletion, splice_region_variant | Exon 14 of 15 | ENST00000352480.10 | NP_446464.1 | |
ASS1 | NM_000050.4 | c.1128_1134delCATGAACinsG | p.Ser376_Asn378delinsArg | missense_variant, conservative_inframe_deletion, splice_region_variant | Exon 15 of 16 | NP_000041.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASS1 | ENST00000352480.10 | c.1128_1134delCATGAACinsG | p.Ser376_Asn378delinsArg | missense_variant, conservative_inframe_deletion, splice_region_variant | Exon 14 of 15 | 1 | NM_054012.4 | ENSP00000253004.6 | ||
ASS1 | ENST00000372393.7 | c.1128_1134delCATGAACinsG | p.Ser376_Asn378delinsArg | missense_variant, conservative_inframe_deletion, splice_region_variant | Exon 15 of 16 | 5 | ENSP00000361469.2 | |||
ASS1 | ENST00000372394.5 | c.1128_1134delCATGAACinsG | p.Ser376_Asn378delinsArg | missense_variant, conservative_inframe_deletion, splice_region_variant | Exon 15 of 16 | 2 | ENSP00000361471.1 | |||
ASS1 | ENST00000372386.6 | n.399_405delCATGAACinsG | splice_region_variant, non_coding_transcript_exon_variant | Exon 5 of 6 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Citrullinemia Pathogenic:1
This variant, c.1128_1134delinsG, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the ASS1 protein (p.Ser376_Asn378delinsArg). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with citrullinemia type I (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ASS1 protein in which other variant(s) (p.Met377Thr) have been determined to be pathogenic (PMID: 35433176). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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