NM_054012.4:c.1128_1134delCATGAACinsG

Variant names:

• chr9-130499505-CATGAAC-G
• rs1439911743
• NM_054012.4:c.1128_1134delCATGAACinsG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM4 PP2 PP5_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: Genomes: not found (cov: 32)
• Consequence: ASS1 NM_054012.4 missense, conservative_inframe_deletion, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.20
• Publications: 2 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: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region 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, adult-onset citrullinemia type I, acute neonatal citrullinemia type I.
• PP5: Variant 9-130499505-CATGAAC-G is Pathogenic according to our data. Variant chr9-130499505-CATGAAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 458671.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	NM_054012.4	MANE Select	c.1128_1134delCATGAACinsG	p.Ser376_Asn378delinsArg	missense conservative_inframe_deletion splice_region	Exon 14 of 15	NP_446464.1
	ASS1	NM_000050.4		c.1128_1134delCATGAACinsG	p.Ser376_Asn378delinsArg	missense conservative_inframe_deletion splice_region	Exon 15 of 16	NP_000041.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASS1	ENST00000352480.10	TSL:1 MANE Select	c.1128_1134delCATGAACinsG	p.Ser376_Asn378delinsArg	missense conservative_inframe_deletion splice_region	Exon 14 of 15	ENSP00000253004.6
	ASS1	ENST00000372393.7	TSL:5	c.1128_1134delCATGAACinsG	p.Ser376_Asn378delinsArg	missense conservative_inframe_deletion splice_region	Exon 15 of 16	ENSP00000361469.2
	ASS1	ENST00000372394.5	TSL:2	c.1128_1134delCATGAACinsG	p.Ser376_Asn378delinsArg	missense conservative_inframe_deletion splice_region	Exon 15 of 16	ENSP00000361471.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Citrullinemia Pathogenic:1

Dec 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

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

Other links and lift over

dbSNP: rs1439911743; hg19: chr9-133374892;