9-130499504-GCATGAAC-GG

Position:

• chr9-130499504-GCATGAAC-GG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_054012.4(ASS1):​c.1128_1134delinsG​(p.Ser376_Asn378delinsArg) variant causes a protein altering, 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 protein_altering, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.20

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_054012.4.
• PP5: Variant 9-130499505-CATGAAC-G is Pathogenic according to our data. Variant chr9-130499505-CATGAAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 458671.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4	c.1128_1134delinsG	p.Ser376_Asn378delinsArg	protein_altering_variant, splice_region_variant	14/15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.1128_1134delinsG	p.Ser376_Asn378delinsArg	protein_altering_variant, splice_region_variant	15/16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.1128_1134delinsG	p.Ser376_Asn378delinsArg	protein_altering_variant, splice_region_variant	14/15	1	NM_054012.4	ENSP00000253004	P1
ASS1	ENST00000372393.7	c.1128_1134delinsG	p.Ser376_Asn378delinsArg	protein_altering_variant, splice_region_variant	15/16	5		ENSP00000361469	P1
ASS1	ENST00000372394.5	c.1128_1134delinsG	p.Ser376_Asn378delinsArg	protein_altering_variant, splice_region_variant	15/16	2		ENSP00000361471	P1
ASS1	ENST00000372386.6	n.399_405delinsG		splice_region_variant, non_coding_transcript_exon_variant	5/6	3

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1439911743; hg19: chr9-133374892;