rs770362721

Variant names:

• chr9-130489385-CG-C
• rs770362721
• NM_054012.4:c.892delG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_054012.4(ASS1):​c.892delG​(p.Glu298ArgfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: ASS1 NM_054012.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.28

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-130489385-CG-C is Pathogenic according to our data. Variant chr9-130489385-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130489385-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.892delG	p.Glu298ArgfsTer18	frameshift_variant	Exon 12 of 15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.892delG	p.Glu298ArgfsTer18	frameshift_variant	Exon 13 of 16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.892delG	p.Glu298ArgfsTer18	frameshift_variant	Exon 12 of 15	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.0000316 AC XY: 23 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrullinemia type I Pathogenic:7

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ASS1 c.892delG (p.Glu298ArgfsTer18) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Glu298ArgfsTer18 variant has been reported in three studies in which it has been found in a compound heterozygous state in four individuals with citrullinemia including two individuals with a missense variant on the second allele and two individuals with another frameshift variant on the second allele (Enns et al. 2005; Martín-Hernández et al. 2014; Diez-Fernandez et al. 2017). One of the individuals with two frameshift variants presented with neonatal onset of neurological damage (Martín-Hernández et al. 2014). The other individual with two frameshift variants also presented as a neonate with elevated citrulline levels and hyperammonemia and died aged five days (Diez-Fernandez et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000016 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage, so the variant is presumed to be rare. Analysis in skin fibroblasts from a patient initially presenting with neurological symptoms post-partum showed undetectable argininosuccinate synthetase activity. A radiolabeled 14C-citrulline/3H-leucine protein incorporation assay confirmed argininosuccinate synthetase deficiency (Enns et al. 2005). Plasma clinical chemistry in this patient show elevated plasma citrulline levels and mild hyperammonemia (Enns et al. 2005). Based on the evidence and the potential impact of frameshift variants, the p.Glu298ArgfsTer18 variant is classified as pathogenic for citrullinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 11, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.892delG variant is predicted to cause a frameshift, which alters the proteins amino acid sequence beginning at position 298 and leads to a premature termination codon 17 amino acids downstream. It is predicted to cause a truncated or absent ASS1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.R389Qfs). One in-silico tool predicts damaging outcome for this variant. This variant is found in 1/121396 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0040825). This variant has been reported in at least two affected individuals. In addition, one clinical laboratory classified this variant as likely pathogenic, without evidence to independently evaluate. Taken together, this variant was classified as pathogenic. -

not provided Pathogenic:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ASS1: PVS1, PM2, PM3, PP4:Moderate -

Apr 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate the variant results in reduced enzyme activity (Zielonka et al., 2019); This variant is associated with the following publications: (PMID: 24508627, 31469252, 15863597, 12815590, 19006241, 25433810) -

Citrullinemia Pathogenic:1

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu298Argfs*18) in the ASS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASS1 are known to be pathogenic (PMID: 18473344, 19006241). This variant is present in population databases (rs770362721, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with citrullinemia type I (PMID: 15863597, 25433810). ClinVar contains an entry for this variant (Variation ID: 188832). 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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs770362721; hg19: chr9-133364772;