9-130480405-G-T

Variant names:

• chr9-130480405-G-T
• rs398123131
• NM_054012.4:c.794G>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_054012.4(ASS1):​c.794G>T​(p.Arg265Leu) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.44

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 11 ACMG points.

• PM1: In a strand (size 6) in uniprot entity ASSY_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_054012.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-130480404-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 9-130480405-G-T is Pathogenic according to our data. Variant chr9-130480405-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1019261.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASS1	NM_054012.4	c.794G>T	p.Arg265Leu	missense_variant	Exon 11 of 15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.794G>T	p.Arg265Leu	missense_variant	Exon 12 of 16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.794G>T	p.Arg265Leu	missense_variant	Exon 11 of 15	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Citrullinemia type I Pathogenic:1

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 08, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Citrullinemia Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 265 of the ASS1 protein (p.Arg265Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ASS1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg265 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18473344, 28132756, 30285816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	.;.;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.97		Loss of MoRF binding (P = 0.0423);Loss of MoRF binding (P = 0.0423);Loss of MoRF binding (P = 0.0423);
MVP		0.97
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.90
gMVP		0.97

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: rs398123131; hg19: chr9-133355792;