9-130458442-C-G

Position:

• chr9-130458442-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_054012.4(ASS1):​c.216C>G​(p.Phe72Leu) variant causes a missense change involving the alteration of a non-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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.24

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 9-130458442-C-G is Pathogenic according to our data. Variant chr9-130458442-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551465.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4	c.216C>G	p.Phe72Leu	missense_variant	4/15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.216C>G	p.Phe72Leu	missense_variant	5/16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.216C>G	p.Phe72Leu	missense_variant	4/15	1	NM_054012.4	ENSP00000253004.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Citrullinemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the ASS1 protein (p.Phe72Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with citrullinemia (PMID: 18925679, 31469252). ClinVar contains an entry for this variant (Variation ID: 551465). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ASS1 protein function. Studies have shown that this missense change alters ASS1 gene expression (PMID: 31469252). This variant disrupts the p.Phe72 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2024	Variant summary: ASS1 c.216C>G (p.Phe72Leu) results in a non-conservative amino acid change located in the Arginosuccinate synthase-like, N-terminal domain (IPR048267) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251016 control chromosomes. c.216C>G has been reported in the literature in homozygous individuals affected with Citrullinemia Type 1, including at least one individual with mild phenotypic presentation (e.g. Dimmock_2008, Zielonka_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduction in mRNA and protein levels and ~80% of normal enzymatic activity (e.g. Zielonka_2019). The following publications have been ascertained in the context of this evaluation (PMID: 18925679, 31469252). ClinVar contains an entry for this variant (Variation ID: 551465). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Citrullinemia type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	2.0	M;M;M;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.51	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.95	P;P;P;.;.
Vest4		0.88
MutPred		0.69		Gain of catalytic residue at F72 (P = 0.011);Gain of catalytic residue at F72 (P = 0.011);Gain of catalytic residue at F72 (P = 0.011);Gain of catalytic residue at F72 (P = 0.011);Gain of catalytic residue at F72 (P = 0.011);
MVP		0.98
MPC		0.90
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.82

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: rs1554982824; hg19: chr9-133333829;