rs786204460

Positions:

• chr9-130499515-C-T

Variant summary

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

The ENST00000352480.10(ASS1):​c.1138C>T​(p.Gln380Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASS1 ENST00000352480.10 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.10

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 9-130499515-C-T is Pathogenic according to our data. Variant chr9-130499515-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130499515-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4	c.1138C>T	p.Gln380Ter	stop_gained	14/15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.1138C>T	p.Gln380Ter	stop_gained	15/16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.1138C>T	p.Gln380Ter	stop_gained	14/15	1	NM_054012.4	ENSP00000253004	P1
ASS1	ENST00000372393.7	c.1138C>T	p.Gln380Ter	stop_gained	15/16	5		ENSP00000361469	P1
ASS1	ENST00000372394.5	c.1138C>T	p.Gln380Ter	stop_gained	15/16	2		ENSP00000361471	P1
ASS1	ENST00000372386.6	n.409C>T		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrullinemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188776). This premature translational stop signal has been observed in individual(s) with citrullinemia (PMID: 12815590). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln380*) 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). -

Citrullinemia type I Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

May 08, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.94
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786204460; hg19: chr9-133374902;