rs869312989

Positions:

• chr7-66086788-T-TGCGGAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The NM_000048.4(ASL):​c.575_580dupAGCGGA​(p.Lys192_Arg193dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASL NM_000048.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0800

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]

ASL (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 25) in uniprot entity ARLY_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000048.4.
• PP5: Variant 7-66086788-T-TGCGGAA is Pathogenic according to our data. Variant chr7-66086788-T-TGCGGAA is described in ClinVar as [Pathogenic]. Clinvar id is 224974.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASL	NM_000048.4	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	8/17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	7/16		NP_001020114.1
ASL	NM_001024944.2	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	7/15		NP_001020115.1
ASL	NM_001024946.2	c.524+132_524+137dupAGCGGA		intron_variant			NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.575_580dupAGCGGA	p.Lys192_Arg193dup	disruptive_inframe_insertion	8/17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

literature only

SNPedia

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312989; hg19: chr7-65551775;