chr9-130458476-G-A

Position:

• chr9-130458476-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_054012.4(ASS1):​c.250G>A​(p.Glu84Lys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASS1 NM_054012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.61

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASS1	NM_054012.4	c.250G>A	p.Glu84Lys	missense_variant	4/15	ENST00000352480.10	NP_446464.1
ASS1	NM_000050.4	c.250G>A	p.Glu84Lys	missense_variant	5/16		NP_000041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASS1	ENST00000352480.10	c.250G>A	p.Glu84Lys	missense_variant	4/15	1	NM_054012.4	ENSP00000253004	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Citrullinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2017

In summary, this variant has uncertain impact on ASS1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a ASS1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 84 of the ASS1 protein (p.Glu84Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	.;.;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.98
MutPred		0.83		Gain of catalytic residue at E84 (P = 0.0465);Gain of catalytic residue at E84 (P = 0.0465);Gain of catalytic residue at E84 (P = 0.0465);Gain of catalytic residue at E84 (P = 0.0465);Gain of catalytic residue at E84 (P = 0.0465);
MVP		0.99
MPC		0.94
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554982834; hg19: chr9-133333863;