9-130458488-CTC-ATA

Variant names:

• chr9-130458488-CTC-ATA
• NM_054012.4:c.262_264delCTCinsATA
• ASS1 p.Leu88Ile

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1_Moderate PM1 PP2

The NM_054012.4(ASS1):​c.262_264delCTCinsATA​(p.Leu88Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L88L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.88
• Publications: 0 publications found

Genes affected

ASS1 (HGNC:758): (argininosuccinate synthase 1) The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2012]

ASS1 Gene-Disease associations (from GenCC):

• citrullinemia type I

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• acute neonatal citrullinemia type I

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• adult-onset citrullinemia type I

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_054012.4 (ASS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_054012.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.75759 (below the threshold of 3.09). Trascript score misZ: 1.8061 (below the threshold of 3.09). GenCC associations: The gene is linked to citrullinemia type I, acute neonatal citrullinemia type I, adult-onset citrullinemia type I.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	NM_054012.4	MANE Select	c.262_264delCTCinsATA	p.Leu88Ile	missense	N/A	NP_446464.1	Q5T6L4
	ASS1	NM_000050.4		c.262_264delCTCinsATA	p.Leu88Ile	missense	N/A	NP_000041.2	P00966

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	ENST00000352480.10	TSL:1 MANE Select	c.262_264delCTCinsATA	p.Leu88Ile	missense	N/A	ENSP00000253004.6	P00966
	ASS1	ENST00000852201.1		c.262_264delCTCinsATA	p.Leu88Ile	missense	N/A	ENSP00000522260.1
	ASS1	ENST00000852207.1		c.262_264delCTCinsATA	p.Leu88Ile	missense	N/A	ENSP00000522266.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-133333875;