NM_000048.4:c.257A>C

Variant names:

• chr7-66082417-A-C
• rs869312986
• NM_000048.4:c.257A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000048.4(ASL):​c.257A>C​(p.Glu86Ala) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.30

Genes affected

ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-66082417-A-C is Pathogenic according to our data. Variant chr7-66082417-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 224971.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-66082417-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.257A>C	p.Glu86Ala	missense_variant	Exon 4 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.257A>C	p.Glu86Ala	missense_variant	Exon 3 of 16		NP_001020114.1
ASL	NM_001024944.2	c.257A>C	p.Glu86Ala	missense_variant	Exon 3 of 15		NP_001020115.1
ASL	NM_001024946.2	c.257A>C	p.Glu86Ala	missense_variant	Exon 3 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.257A>C	p.Glu86Ala	missense_variant	Exon 4 of 17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:1

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SNPedia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;H;H;.;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.94
MutPred		0.96		Loss of solvent accessibility (P = 0.0159);Loss of solvent accessibility (P = 0.0159);Loss of solvent accessibility (P = 0.0159);.;Loss of solvent accessibility (P = 0.0159);
MVP		0.99
MPC		0.96
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.97
gMVP		0.94

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: rs869312986; hg19: chr7-65547404;