rs1085307056

Positions:

• chr9-130479716-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_054012.4(ASS1):​c.689G>C​(p.Gly230Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G230R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASS1 NM_054012.4 missense, splice_region
• Scores: Splicing: ADA: 0.9682
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.77

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 9-130479716-G-C is Pathogenic according to our data. Variant chr9-130479716-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASS1	NM_054012.4	c.689G>C	p.Gly230Ala	missense_variant, splice_region_variant	10/15	ENST00000352480.10
ASS1	NM_000050.4	c.689G>C	p.Gly230Ala	missense_variant, splice_region_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASS1	ENST00000352480.10	c.689G>C	p.Gly230Ala	missense_variant, splice_region_variant	10/15	1	NM_054012.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrullinemia type I Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic/likely pathogenic with supporting evidence (PMID: 23099195, PS1_P). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.923, 3Cnet: 0.995, PP3). Patient is considered compatible with Snijders Citrullinemia (PP4_P).Therefore, this variant is classified as likley pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.3	H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.57	P;P;P
Vest4		0.98
MutPred		0.95		Loss of catalytic residue at V231 (P = 0.1577);Loss of catalytic residue at V231 (P = 0.1577);Loss of catalytic residue at V231 (P = 0.1577);
MVP		0.98
MPC		0.49
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.94
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.83
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: rs1085307056; hg19: chr9-133355103;